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Entry
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- *176943 - FIBROBLAST GROWTH FACTOR RECEPTOR 2; FGFR2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*176943</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/176943">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000066468;t=ENST00000358487" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=2263" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=176943" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000066468;t=ENST00000358487" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000141,NM_001144913,NM_001144914,NM_001144915,NM_001144916,NM_001144917,NM_001144918,NM_001144919,NM_001320654,NM_001320658,NM_022970,NM_023029,NR_073009,XM_006717708,XM_006717710,XM_017015920,XM_017015921,XM_017015924,XM_017015925,XM_024447887,XM_024447888,XM_024447889,XM_024447890,XM_024447891" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000141" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=176943" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01492&isoform_id=01492_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/FGFR2" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/29432,31374,120049,182567,186741,186780,186782,186784,232796,232800,232811,339711,530802,1129107,1129109,1129111,1129113,1129115,1129117,1296625,3077607,4262092,4883533,4883534,4883535,4883536,4883537,4883538,4883539,4883540,6691445,6691447,6691449,6691451,6691453,6691455,7243324,7243325,7765072,7765073,13186243,15281414,15281415,15281416,15281417,15281418,21667446,27260913,73909111,77157500,92918935,119569723,119569724,119569725,119569726,119569727,119569728,119569729,119569730,119569731,119569732,119569733,119569734,119569735,119569736,119569737,119569738,119569739,119569740,119569741,119569742,119569743,119569744,119569745,126636208,194318492,194318494,194318496,194318498,194376078,221316638,221316639,222144231,222144233,222144235,222144237,222144239,222144241,222144244,307334913,444738097,444738099,578819115,578819119,785935696,785935698,785935700,785935702,785935704,785935706,785935708,785935710,785935712,1002341823,1002341835,1034567208,1034567210,1034567216,1034567218,1370456685,1370456687,1370456689,1370456691,1370456693,2462517757,2462517759,2462517761,2462517763,2462517765,2462517767,2462517769,2462517771,2462517773,2462517775,2462517777" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P21802" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=2263" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000066468;t=ENST00000358487" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=FGFR2" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=FGFR2" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+2263" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/FGFR2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:2263" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2263" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr10&hgg_gene=ENST00000457416.7&hgg_start=121478330&hgg_end=121598458&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:3689" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/fgfr2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176943[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176943[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FGFR2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000066468" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=FGFR2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=FGFR2" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=FGFR2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FGFR2&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA28128" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:3689" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0010389.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:95523" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/FGFR2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:95523" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/2263/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002090/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2263" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001184;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030323-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2263" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FGFR2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 205258009, 62964007, 703528008, 70410008, 709105005, 83015004<br />
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<strong>ICD10CM:</strong> Q87.0<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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176943
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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FIBROBLAST GROWTH FACTOR RECEPTOR 2; FGFR2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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FGF RECEPTOR<br />
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PROTEIN TYROSINE KINASE, RECEPTOR-LIKE, 14; TK14
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<span class="h3 mim-font">
|
|
KERATINOCYTE GROWTH FACTOR RECEPTOR, INCLUDED; KGFR, INCLUDED
|
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</span>
|
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</div>
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<div>
|
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<span class="h4 mim-font">
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|
|
BEK, MOUSE, HOMOLOG OF, INCLUDED<br />
|
|
FIBROBLAST GROWTH FACTOR RECEPTOR BEK, INCLUDED
|
|
</span>
|
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</div>
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</div>
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<div>
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FGFR2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FGFR2</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/10/618?start=-3&limit=10&highlight=618">10q26.13</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:121478330-121598458&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">10:121,478,330-121,598,458</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=609579,207410,101200,123790,614592,101600,123500,613659,123150,149730,101600,101400," class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="14">
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<span class="mim-font">
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<a href="/geneMap/10/618?start=-3&limit=10&highlight=618">
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10q26.13
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Scaphocephaly, maxillary retrusion, and impaired intellectual development
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
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</span>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/609579"> 609579 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/207410"> 207410 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
|
</td>
|
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</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Apert syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/101200"> 101200 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Beare-Stevenson cutis gyrata syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/123790"> 123790 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Bent bone dysplasia syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614592"> 614592 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Craniofacial-skeletal-dermatologic dysplasia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/101600"> 101600 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Craniosynostosis, nonspecific
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Crouzon syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/123500"> 123500 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Gastric cancer, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613659"> 613659 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Jackson-Weiss syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/123150"> 123150 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
LADD syndrome 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/149730"> 149730 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pfeiffer syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/101600"> 101600 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Saethre-Chotzen syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/101400"> 101400 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Scaphocephaly and Axenfeld-Rieger anomaly
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
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|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/176943" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/176943" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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|
|
|
|
|
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|
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</div>
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
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|
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<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
|
|
|
|
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|
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<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
|
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
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<span class="mim-text-font">
|
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<p><a href="#34" class="mim-tip-reference" title="Houssaint, E., Blanquet, P. R., Champion-Arnaud, P., Gesnel, M. C., Torriglia, A., Courtois, Y., Breathnach, R. <strong>Related fibroblast growth factor receptor genes exist in the human genome.</strong> Proc. Nat. Acad. Sci. 87: 8180-8184, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2172978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2172978</a>] [<a href="https://doi.org/10.1073/pnas.87.20.8180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2172978">Houssaint et al. (1990)</a> isolated a gene encoding a putative receptor-like protein-tyrosine kinase, which the authors called TK14, from a human tumor cDNA library. The deduced amino acid sequence was closely related to that of the mouse protein bek (bacterially expressed kinase), and more distantly related to the sequences of a chicken basic fibroblast growth factor receptor (73% sequence homology) and its presumed human equivalent, the FLG protein (<a href="/entry/136350">136350</a>). Overexpression of the TK14 protein by transfection of COS-1 cells led to the appearance of new cell-surface binding sites for both acidic and basic fibroblast growth factors. <a href="#16" class="mim-tip-reference" title="Dionne, C. A., Crumley, G., Bellot, F., Kaplow, J. M., Searfoss, G., Ruta, M., Burgess, W. H., Jaye, M., Schlessinger, J. <strong>Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors.</strong> EMBO J. 9: 2685-2692, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1697263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1697263</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07454.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1697263">Dionne et al. (1990)</a> also cloned a complete cDNA for the human bek homolog (symbolized FGFR2). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2172978+1697263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Keratinocyte growth factor (<a href="/entry/148180">148180</a>) has potent mitogenic activity for a wide variety of epithelial cells but lacks detectable activity on fibroblasts or endothelial cells. This synthesis by stromal fibroblasts in a large number of epithelial tissues suggests that KGF is an important paracrine mediator of normal epithelial cell proliferation. Furthermore, studies indicated specific KGF binding to keratinocytes but not fibroblasts. <a href="#59" class="mim-tip-reference" title="Miki, T., Fleming, T. P., Bottaro, D. P., Rubin, J. S., Ron, D., Aaronson, S. A. <strong>Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop.</strong> Science 251: 72-75, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1846048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1846048</a>] [<a href="https://doi.org/10.1126/science.1846048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1846048">Miki et al. (1991)</a> devised an expression cloning strategy to isolate cDNA for the keratinocyte growth factor receptor. The 4.2-kb cDNA was shown to encode a predicted membrane-spanning tyrosine kinase related to, but distinct from, the basic FGF receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1846048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
|
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</span>
|
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<div>
|
|
<br />
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<p>The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain. The other fibroblast growth factor receptors that have been identified are FGFR1 (<a href="/entry/136350">136350</a>); FGFR3 (<a href="/entry/134934">134934</a>), which is mutant in achondroplasia (<a href="/entry/100800">100800</a>); and FGFR4 (<a href="/entry/134935">134935</a>). Sequence analysis of the 4.5-kb human FGFR2 gene shows an open reading frame encoding the typical membrane-spanning, tyrosine kinase receptor structure of the FGFR gene family. Two alternative gene products have been characterized: KGFR and BEK. These 2 isoforms are identical except for a 49-amino acid sequence spanning the second half of the third Ig loop in the extracellular region. This local diversity is due to the presence of alternative exons within FGFR2, exon B being expressed in the BEK product and exon K26 in KGFR. Control of these alternative splice sites is thought to involve transacting factors (<a href="#23" class="mim-tip-reference" title="Gilbert, E., Del Gatto, F., Champion-Arnaud, P., Gesnel, M.-C., Breathnach, R. <strong>Control of BEK and K-SAM splice sites in alternative splicing of the fibroblast growth factor receptor 2 pre-mRNA.</strong> Molec. Cell. Biol. 13: 5461-5468, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355693</a>] [<a href="https://doi.org/10.1128/mcb.13.9.5461-5468.1993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8355693">Gilbert et al., 1993</a>). The variation in expressed gene product is highly significant because the ligand-binding characteristics of KGFR and BEK are quite distinct. Furthermore, they have different patterns of expression in murine embryogenesis. Whereas KGFR appears to have a role in skin development, BEK is preferentially expressed in osteogenesis. BEK transcripts are concentrated in the frontal bones, maxilla, mandibula, and ossicles of the middle ear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8355693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Wilkie, A. O. M., Slaney, S. F., Oldridge, M., Poole, M. D., Ashworth, G. J., Hockley, A. D., Hayward, R. D., David, D. J., Pulleyn, L. J., Rutland, P., Malcolm, S., Winter, R. M., Reardon, W. <strong>Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.</strong> Nature Genet. 9: 165-172, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719344</a>] [<a href="https://doi.org/10.1038/ng0295-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719344">Wilkie et al. (1995)</a> provided a useful resume of the 4 different systems that have been used for numbering exons in the FGFR genes and the cDNA nucleotide numbering system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7719344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#62" class="mim-tip-reference" title="Moore, K. B., Mood, K., Daar, I. O., Moody, S. A. <strong>Morphogenetic movements underlying eye field formation require interactions between the FGF and ephrinB1 signaling pathways.</strong> Dev. Cell 6: 55-67, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14723847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14723847</a>] [<a href="https://doi.org/10.1016/s1534-5807(03)00395-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14723847">Moore et al. (2004)</a> studied the role of FGF and ephrin signaling in retina development in the frog. Activation of Fgfr2 signaling before gastrulation repressed cellular movements in the presumptive anterior neural plate and prevented normal retinal progenitor cells from adopting retinal fates. Ephrin B1 (<a href="/entry/300035">300035</a>) signaling during gastrulation was required for retinal progenitors to move into the eye field, and this movement could be modified by activating the FGF pathway. <a href="#62" class="mim-tip-reference" title="Moore, K. B., Mood, K., Daar, I. O., Moody, S. A. <strong>Morphogenetic movements underlying eye field formation require interactions between the FGF and ephrinB1 signaling pathways.</strong> Dev. Cell 6: 55-67, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14723847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14723847</a>] [<a href="https://doi.org/10.1016/s1534-5807(03)00395-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14723847">Moore et al. (2004)</a> concluded that FGF modulation of ephrin signaling is important for establishing the bona fide retinal progenitors in the anterior neural plate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14723847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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To elucidate the structural determinants governing specificity in FGF signaling, <a href="#78" class="mim-tip-reference" title="Plotnikov, A. N., Hubbard, S. R., Schlessinger, J., Mohammadi, M. <strong>Crystal structures of two FGF-FGFR complexes reveal the determinants of ligand-receptor specificity.</strong> Cell 101: 413-424, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10830168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10830168</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80851-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10830168">Plotnikov et al. (2000)</a> determined the crystal structures of FGF1 (<a href="/entry/131220">131220</a>) and FGF2 (<a href="/entry/134920">134920</a>) complexed with the immunoglobulin-like ligand-binding domains 2 and 3 (D2 and D3) of FGFR1 and FGFR2, respectively. They found that highly conserved FGF-D2 and FGF-linker (between D2 and D3) interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and 2 loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10830168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Pellegrini, L., Burke, D. F., von Delft, F., Mulloy, B., Blundell, T. L. <strong>Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin.</strong> Nature 407: 1029-1034, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11069186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11069186</a>] [<a href="https://doi.org/10.1038/35039551" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11069186">Pellegrini et al. (2000)</a> reported the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide. The complex is assembled around a central heparin molecule linking 2 FGF1 ligands into a dimer that bridges between 2 receptor chains. The asymmetric heparin binding involves contacts with both FGF1 molecules but only one receptor chain. The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulfate in FGF signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11069186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>FGF-FGFR binding specificity is essential for mammalian development and is regulated primarily by 2 alternatively spliced exons, IIIb (b) and IIIc (c), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). <a href="#118" class="mim-tip-reference" title="Yeh, B. K., Igarashi, M., Eliseenkova, A. V., Plotnikov, A. N., Sher, I., Ron, D., Aaronson, S. A., Mohammadi, M. <strong>Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors.</strong> Proc. Nat. Acad. Sci. 100: 2266-2271, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12591959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12591959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12591959[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0436500100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12591959">Yeh et al. (2003)</a> reported the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions of FGF10 and 2 b-specific loops in D3 revealed the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirmed the importance of the observed contacts for FGF10 biologic activity. FGF10 binding induced a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. <a href="#118" class="mim-tip-reference" title="Yeh, B. K., Igarashi, M., Eliseenkova, A. V., Plotnikov, A. N., Sher, I., Ron, D., Aaronson, S. A., Mohammadi, M. <strong>Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors.</strong> Proc. Nat. Acad. Sci. 100: 2266-2271, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12591959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12591959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12591959[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0436500100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12591959">Yeh et al. (2003)</a> proposed that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12591959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#53" class="mim-tip-reference" title="Mattei, M.-G., Moreau, A., Gesnel, M.-C., Houssaint, E., Breathnach, R. <strong>Assignment by in situ hybridization of a fibroblast growth factor receptor gene to human chromosome band 10q26.</strong> Hum. Genet. 87: 84-86, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1674718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1674718</a>] [<a href="https://doi.org/10.1007/BF01213098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1674718">Mattei et al. (1991)</a> used a 2.3-kb cDNA probe from the human BEK fibroblast growth factor receptor to determine localization of the gene on chromosome 10q26 by in situ hybridization. <a href="#17" class="mim-tip-reference" title="Dionne, C. A., Modi, W. S., Crumley, G., O'Brien, S. J., Schlessinger, J., Jaye, M. <strong>BEK, a receptor for multiple members of the fibroblast growth factor (FGF) family, maps to human chromosome 10q25.3-q26.</strong> Cytogenet. Cell Genet. 60: 34-36, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1582255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1582255</a>] [<a href="https://doi.org/10.1159/000133290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1582255">Dionne et al. (1992)</a> assigned the BEK gene to chromosome 10 by applying PCR techniques to DNAs from a panel of human/rodent somatic cell hybrids. They further localized the gene to chromosome 10q25.3-q26 by in situ hybridization. Using an interspecific backcross mapping panel, <a href="#6" class="mim-tip-reference" title="Avraham, K. B., Givol, D., Avivi, A., Yayon, A., Copeland, N. G., Jenkins, N. A. <strong>Mapping of murine fibroblast growth factor receptors refines regions of homology between mouse and human chromosomes.</strong> Genomics 21: 656-658, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959747</a>] [<a href="https://doi.org/10.1006/geno.1994.1330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959747">Avraham et al. (1994)</a> mapped the murine equivalent to chromosome 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7959747+1582255+1674718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Because of the clear importance of BEK expression in osteogenesis and the localization of FGFR2 to the same chromosomal region as the mutation responsible for Crouzon syndrome (CFD1; <a href="/entry/123500">123500</a>), FGFR2 became a candidate gene for the clinical disorder. <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found SSCP variations in the B exon of FGFR2 in 9 unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in 3 unrelated multigeneration families. In 4 sporadic cases, the unaffected parents did not have SSCP variation. Direct sequencing revealed specific mutations in the B exon in all 9 sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in 5 patients. In only 9 out of 20 patients with Crouzon syndrome did <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> find mutations in the FGFR2 gene. There was, however, no evidence for genetic heterogeneity either in a previously published linkage report (<a href="#80" class="mim-tip-reference" title="Preston, R. A., Post, J. C., Keats, B. J. B., Aston, C. E., Ferrell, R. E., Priest, J., Nouri, N., Losken, H. W., Morris, C. A., Hurtt, M. R., Mulvihill, J. J., Ehrlich, G. D. <strong>A gene for Crouzon craniofacial dysostosis maps to the long arm of chromosome 10.</strong> Nature Genet. 7: 149-153, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7920632/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7920632</a>] [<a href="https://doi.org/10.1038/ng0694-149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7920632">Preston et al., 1994</a>) or in the new data. It was thought likely that mutations in other areas of the FGFR2 gene were responsible for the cases yet to be explained. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7920632+7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> demonstrated mutations in the FGFR2 gene in patients with Crouzon syndrome as well as in patients with Jackson-Weiss syndrome (JWS; <a href="/entry/123150">123150</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Wilkie, A. O. M., Slaney, S. F., Oldridge, M., Poole, M. D., Ashworth, G. J., Hockley, A. D., Hayward, R. D., David, D. J., Pulleyn, L. J., Rutland, P., Malcolm, S., Winter, R. M., Reardon, W. <strong>Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.</strong> Nature Genet. 9: 165-172, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719344</a>] [<a href="https://doi.org/10.1038/ng0295-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719344">Wilkie et al. (1995)</a> found mutations in the FGFR2 gene in Apert syndrome (<a href="/entry/101200">101200</a>). In all 40 unrelated cases of Apert syndrome studied, they identified specific missense substitutions involving adjacent amino acids (ser252-to-trp, <a href="#0010">176943.0010</a> and pro253-to-arg, <a href="#0011">176943.0011</a>) in the linker between the second and third extracellular immunoglobulin (Ig) domains of FGFR2. The first of these mutations was caused by a C-to-G transversion at position 934 of the cDNA. The second was caused by a C-to-G transversion at position 937. <a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> referred to these as the type 1 and type 2 mutations, respectively. The 934C-G mutation arose in a CpG dinucleotide, whereas the 937C-G mutation did not. The fact that they did not observe any 934C-T mutations (ser252-to-leu) suggested that this would give a phenotype different from that of Apert syndrome. <a href="#112" class="mim-tip-reference" title="Wilkie, A. O. M., Slaney, S. F., Oldridge, M., Poole, M. D., Ashworth, G. J., Hockley, A. D., Hayward, R. D., David, D. J., Pulleyn, L. J., Rutland, P., Malcolm, S., Winter, R. M., Reardon, W. <strong>Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.</strong> Nature Genet. 9: 165-172, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719344</a>] [<a href="https://doi.org/10.1038/ng0295-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719344">Wilkie et al. (1995)</a> found the type 1 mutation in 25 of the patients and the type 2 mutation in 15. In 3 patients, the parental origin of new mutations was established to be the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874170+7719344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a larger series of 118 unrelated cases of Apert syndrome studied in Oxford, <a href="#61" class="mim-tip-reference" title="Moloney, D. M., Slaney, S. F., Oldridge, M., Wall, S. A., Sahlin, P., Stenman, G., Wilkie, A. O. M. <strong>Exclusive paternal origin of new mutations in Apert syndrome.</strong> Nature Genet. 13: 48-53, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673103</a>] [<a href="https://doi.org/10.1038/ng0596-48" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673103">Moloney et al. (1996)</a> found that 74 had the 934C-G mutation and 44 had the 937C-G mutation. Combined with the cases reported by <a href="#71" class="mim-tip-reference" title="Park, W.-J., Meyers, G. A., Li, X., Theda, C., Day, D., Orlow, S. J., Jones, M. C., Jabs, E. W. <strong>Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.</strong> Hum. Molec. Genet. 4: 1229-1233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528214</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528214">Park et al. (1995)</a>, the total experience indicated that 108 of 166 cases (65%) were of the 934C-G type, 57 of 166 cases (34%) were of the 937C-G type, and 1 case observed by <a href="#71" class="mim-tip-reference" title="Park, W.-J., Meyers, G. A., Li, X., Theda, C., Day, D., Orlow, S. J., Jones, M. C., Jabs, E. W. <strong>Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.</strong> Hum. Molec. Genet. 4: 1229-1233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528214</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528214">Park et al. (1995)</a> was of unknown mutational basis. <a href="#113" class="mim-tip-reference" title="Wilkie, A. O. M. <strong>Personal Communication.</strong> Oxford, U.K. 2/24/1996."None>Wilkie (1996)</a> observed paternal age effect with both Apert mutations in 54 informative families; the mutation was of paternal origin in all cases. Limb malformation seemed to be more severe in the 937C-G mutation; cleft palate was more often present, and craniofacial abnormality was in general more severe with the 934C-G mutation (<a href="#113" class="mim-tip-reference" title="Wilkie, A. O. M. <strong>Personal Communication.</strong> Oxford, U.K. 2/24/1996."None>Wilkie, 1996</a>). Indeed, the severe craniofacial abnormality and cleft palate in association with milder involvement of the hands gave rise to the designation of Vogt cephalodactyly or Apert-Crouzon disease for the condition in the cases described by <a href="#107" class="mim-tip-reference" title="Vogt, A. <strong>Dyskephalie (dysostosis craniofacialis, maladie De Crouzon 1912) und eine neuartige Kombination dieser Krankheit mit Syndaktylie der 4 Extremitaeten (Dyskephalodaktylie).</strong> Klin. Monatsbl. Augenheilkd. 90: 441-454, 1933."None>Vogt (1933)</a> combining the hand and foot malformations characteristic of Apert disease with the facial characteristics of Crouzon disease; see <a href="/entry/101200">101200</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528214+8673103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Lajeunie, E., Ma, H. W., Bonaventure, J., Munnich, A., Le Merrer, M., Renier, D. <strong>FGFR2 mutations in Pfeiffer syndrome. (Letter)</strong> Nature Genet. 9: 108 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719333</a>] [<a href="https://doi.org/10.1038/ng0295-108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719333">Lajeunie et al. (1995)</a> and <a href="#88" class="mim-tip-reference" title="Rutland, P., Pulleyn, L. J., Reardon, W., Baraitser, M., Hayward, R., Jones, B., Malcolm, S., Winter, R. M., Oldridge, M., Slaney, S. F., Poole, M. D., Wilkie, A. O. M. <strong>Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.</strong> Nature Genet. 9: 173-176, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719345</a>] [<a href="https://doi.org/10.1038/ng0295-173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719345">Rutland et al. (1995)</a> found mutations in the FGFR2 gene in some patients with Pfeiffer syndrome (<a href="/entry/101600">101600</a>). In the instance of some mutations, the disorder was Pfeiffer syndrome in some families and Crouzon syndrome in others. Thus, mutations in the FGFR2 gene may result in any one of several different phenotypes. The clinical criteria of Pfeiffer syndrome, particularly interphalangeal ankylosis, are thought to be distinctive (<a href="#48" class="mim-tip-reference" title="Lajeunie, E., Ma, H. W., Bonaventure, J., Munnich, A., Le Merrer, M., Renier, D. <strong>FGFR2 mutations in Pfeiffer syndrome. (Letter)</strong> Nature Genet. 9: 108 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719333</a>] [<a href="https://doi.org/10.1038/ng0295-108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719333">Lajeunie et al., 1995</a>). There is no confusion of Pfeiffer syndrome with Crouzon syndrome, in which no hand anomalies and occasional radial-ulnar synostosis have been reported, or with Jackson-Weiss syndrome, which includes a tarsal-metatarsal coalescence and a medial deviation of broad great toes. The occurrence of different phenotypes with the same mutation may reflect the presence on the same chromosome of a particular change elsewhere in the gene. This would be comparable to the asp178-to-asn mutation in the prion protein gene (<a href="/entry/176640">176640</a>), which results in familial fatal insomnia (<a href="/entry/600072">600072</a>) when the amino acid at position 129 is methionine, and in Creutzfeldt-Jakob disease (<a href="/entry/123400">123400</a>) when the amino acid at position 129 is valine. <a href="#63" class="mim-tip-reference" title="Mulvihill, J. J. <strong>Craniofacial syndromes: no such thing as a single gene disease.</strong> Nature Genet. 9: 101-103, 1995. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719329</a>] [<a href="https://doi.org/10.1038/ng0295-101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719329">Mulvihill (1995)</a> commented that in statistical parlance, some clinical diagnoses of syndromes of multiple malformations are more like confidence intervals than point estimates. He suggested further that permutation may be a better term than mutation. With over 100 craniosynostosis syndromes, 9 fibroblast growth factors, and 4 receptors for them, each with many overlapping and homologous regions, combination and permutation may lead to the inevitable failure of the one mutation-one disease model. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7719345+7719333+7719329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 39 unrelated patients with Crouzon, Jackson-Weiss, or Pfeiffer syndrome, <a href="#58" class="mim-tip-reference" title="Meyers, G. A., Day, D., Goldberg, R., Daentl, D. L., Przylepa, K. A., Abrams, L. J., Graham, J. M., Jr., Feingold, M., Moeschler, J. B., Rawnsley, E., Scott, A. F., Jabs, E. W. <strong>FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.</strong> Am. J. Hum. Genet. 58: 491-498, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644708</a>]" pmid="8644708">Meyers et al. (1996)</a> identified 11 mutations in exon IIIa or exon IIIc in 17 patients. Although previous studies had identified mutations in exon IIIa only in Crouzon syndrome patients, <a href="#58" class="mim-tip-reference" title="Meyers, G. A., Day, D., Goldberg, R., Daentl, D. L., Przylepa, K. A., Abrams, L. J., Graham, J. M., Jr., Feingold, M., Moeschler, J. B., Rawnsley, E., Scott, A. F., Jabs, E. W. <strong>FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.</strong> Am. J. Hum. Genet. 58: 491-498, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644708</a>]" pmid="8644708">Meyers et al. (1996)</a> identified them in Jackson-Weiss and Pfeiffer syndrome patients as well. <a href="#97" class="mim-tip-reference" title="Steinberger, D., Mulliken, J. B., Muller, U. <strong>Crouzon syndrome: previously unrecognized deletion, duplication, and point mutation within FGFR2 gene.</strong> Hum. Mutat. 8: 386-390, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8956050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8956050</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:4<386::AID-HUMU18>3.0.CO;2-Z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8956050">Steinberger et al. (1996)</a> identified previously unrecognized mutations in each of 3 patients with Crouzon syndrome: a deletion, a duplication, and a point mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8956050+8644708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#98" class="mim-tip-reference" title="Steinberger, D., Reinhartz, T., Unsold, R., Muller, U. <strong>FGFR2 mutation in clinically nonclassifiable autosomal dominant craniosynostosis with pronounced phenotypic variation.</strong> Am. J. Med. Genet. 66: 81-86, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8957519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8957519</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961202)66:1<81::AID-AJMG19>3.0.CO;2-M" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8957519">Steinberger et al. (1996)</a> described an FGFR2 mutation (<a href="#0006">176943.0006</a>) in a large family with autosomal dominant craniosynostosis with marked phenotypic variation and with clinical manifestations that were not classifiable as Apert, Crouzon, Pfeiffer, or Jackson-Weiss syndromes. The mutation detected in the family described by <a href="#97" class="mim-tip-reference" title="Steinberger, D., Mulliken, J. B., Muller, U. <strong>Crouzon syndrome: previously unrecognized deletion, duplication, and point mutation within FGFR2 gene.</strong> Hum. Mutat. 8: 386-390, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8956050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8956050</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1996)8:4<386::AID-HUMU18>3.0.CO;2-Z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8956050">Steinberger et al. (1996)</a> is identical to that described in a family with Crouzon syndrome by <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> and by <a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874170+8956050+7987400+8957519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Oldridge, M., Lunt, P. W., Zackai, E. H., McDonald-McGinn, D. M., Muenke, M., Moloney, D. M., Twigg, S. R. F., Heath, J. K., Howard, T. D., Hoganson, G., Gagnon, D. M., Jabs, E. W., Wilkie, A. O. M. <strong>Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.</strong> Hum. Molec. Genet. 6: 137-143, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002682</a>] [<a href="https://doi.org/10.1093/hmg/6.1.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002682">Oldridge et al. (1997)</a> stated that recurrent mutations of a serine-proline dipeptide (either ser252 to trp or pro253 to arg) had been identified in more than 160 unrelated individuals with Apert syndrome. They identified 3 novel mutations of this dipeptide associated with distinct phenotypes. The substitution ser252leu was demonstrated in a boy with mild Crouzon syndrome and was also present in 3 clinically normal members of his family. A CG-to-TT mutation that predicted a ser252-to-phe substitution (<a href="#0017">176943.0017</a>) resulted in a phenotype consistent with Apert syndrome. Finally, a CGC-to-TCT mutation that predicted a double amino acid substitution (ser252 to phe and pro253 to ser; <a href="#0018">176943.0018</a>) caused a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the ser252-to-phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlighted the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. <a href="#67" class="mim-tip-reference" title="Oldridge, M., Lunt, P. W., Zackai, E. H., McDonald-McGinn, D. M., Muenke, M., Moloney, D. M., Twigg, S. R. F., Heath, J. K., Howard, T. D., Hoganson, G., Gagnon, D. M., Jabs, E. W., Wilkie, A. O. M. <strong>Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.</strong> Hum. Molec. Genet. 6: 137-143, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002682</a>] [<a href="https://doi.org/10.1093/hmg/6.1.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002682">Oldridge et al. (1997)</a> stated that the substitution ser252 to phe was the first noncanonical mutation to be identified in Apert syndrome, its rarity being explained by the requirement for 2 residues of the serine codon to be mutated. The authors noted that they had previously demonstrated exclusive paternal origin of mutation in Apert syndrome in 57 of 57 cases, and suggested that the high apparent rates for several FGFR mutations could arise by a selective advantage conferred to the mutated male germ cell (<a href="#61" class="mim-tip-reference" title="Moloney, D. M., Slaney, S. F., Oldridge, M., Wall, S. A., Sahlin, P., Stenman, G., Wilkie, A. O. M. <strong>Exclusive paternal origin of new mutations in Apert syndrome.</strong> Nature Genet. 13: 48-53, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673103</a>] [<a href="https://doi.org/10.1038/ng0596-48" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673103">Moloney et al., 1996</a>). Consistent with this, there is evidence that the FGF/FGFR signaling pathway plays an important role in the initiation and maintenance of spermatogenesis (<a href="#105" class="mim-tip-reference" title="Van Dissel-Emiliani, F. M., De Boer-Brouwer, M., De Rooij, D. G. <strong>Effect of fibroblast growth factor-2 on Sertoli cells and gonocytes in coculture during the perinatal period.</strong> Endocrinology 137: 647-654, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8593814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8593814</a>] [<a href="https://doi.org/10.1210/endo.137.2.8593814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8593814">Van Dissel-Emiliani et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8593814+9002682+8673103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Goriely, A., McVean, G. A. T., Rojmyr, M., Ingemarsson, B., Wilkie, A. O. M. <strong>Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.</strong> Science 301: 643-646, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12893942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12893942</a>] [<a href="https://doi.org/10.1126/science.1085710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12893942">Goriely et al. (2003)</a> developed a sensitive method to quantify substitutions at nucleotide 755 of the FGFR2 gene, which lead to mutations in codon 252, in sperm. They measured mutation levels in samples from blood of 11 healthy individuals, sperm from 99 healthy men without a family history of Apert syndrome, and sperm from 6 unaffected fathers of children with Apert syndrome caused by the 755C-G mutation. Only low levels (less than 10(-5)) of all mutations were found in blood, which excluded the possibility that higher levels in sperm were caused by contamination or PCR artifacts. In sperm, the level of 755C-A never exceeded 6.3 x 10(-6) and showed no paternal age effects (r of -0.06; p of 0.71), but both 755C-G and 755C-T reached high levels (maxima of 1.6 x 10(-4) and 1.4 x 10(-4), respectively) that were positively correlated with donor age. The average level of 755C-G was 1.66-fold higher than that of 755C-T, which was statistically significant. Levels of the 755C-G mutation in the sperm of fathers of Apert syndrome children were also within the envelope of normal values, indicating that these men were sampled from the general population and had a very low risk of fathering another affected child. Further analyses led <a href="#27" class="mim-tip-reference" title="Goriely, A., McVean, G. A. T., Rojmyr, M., Ingemarsson, B., Wilkie, A. O. M. <strong>Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.</strong> Science 301: 643-646, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12893942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12893942</a>] [<a href="https://doi.org/10.1126/science.1085710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12893942">Goriely et al. (2003)</a> to conclude that the major factor underlying the paternal age effect is not the accumulation of replication errors or insufficient repair processes, but positive selection of infrequent mutations acting over the course of time. They stated that the constancy of FGFR2 mutation levels over many months indicated that the mutations are present in spermatogonia with stem cell-like properties. <a href="#27" class="mim-tip-reference" title="Goriely, A., McVean, G. A. T., Rojmyr, M., Ingemarsson, B., Wilkie, A. O. M. <strong>Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.</strong> Science 301: 643-646, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12893942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12893942</a>] [<a href="https://doi.org/10.1126/science.1085710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12893942">Goriely et al. (2003)</a> proposed that these FGFR2 mutations, although harmful to embryonic development, are paradoxically enriched because they confer selective advantage to the spermatogonial cells in which they arise. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12893942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Glaser, R. L., Broman, K. W., Schulman, R. L., Eskenazi, B., Wyrobek, A. J., Jabs, E. W. <strong>The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm.</strong> Am. J. Hum. Genet. 73: 939-947, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12900791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/378419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12900791">Glaser et al. (2003)</a> studied the paternal age effect and the exclusive paternal origin of mutations reported in Apert syndrome. As the incidence of sporadic Apert syndrome births increases exponentially with paternal age, they hypothesized that the frequency of Apert syndrome mutations in sperm would also increase. They noted that 99% of sporadic cases of Apert syndrome are caused by 1 of 2 common mutations in the FGFR2 gene, S252W (<a href="#0010">176943.0010</a>) or P253R (<a href="#0011">176943.0011</a>), and developed allele-specific peptide nucleic acid PCR assays to determine the frequency of these 2 mutations. Analyzing sperm DNA from 148 men, aged 21 to 80 years, they showed that the number of sperm with mutations increased in the oldest age groups among men who did not have a child with Apert syndrome. These older men were also more likely to have both mutations in their sperm. However, this age-related increase in mutation frequency was not sufficient to explain the Apert syndrome birth frequency. In contrast, the mutation frequency observed in men who were younger and had children with Apert syndrome was significantly greater. The data suggested selection for sperm with specific mutations. Therefore, contributing factors to the paternal age effect may include selection and a higher number of mutant sperm in a subset of men ascertained because they had a child with Apert syndrome. No age-related increase in the frequency of these mutations was observed in leukocytes. Selection and/or quality control mechanisms, including DNA repair and apoptosis, may contribute to the cell type differences in mutation frequency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of sporadic cases of Crouzon syndrome and Pfeiffer syndrome, <a href="#25" class="mim-tip-reference" title="Glaser, R. L., Jiang, W., Boyadjiev, S. A., Tran, A. K., Zachary, A. A., Van Maldergem, L., Johnson, D., Walsh, S., Oldridge, M., Wall, S. A., Wilkie, A. O. M., Jabs, E. W. <strong>Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome.</strong> Am. J. Hum. Genet. 66: 768-777, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712195/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712195</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712195[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712195">Glaser et al. (2000)</a> used 4 intragenic polymorphisms to screen a total of 41 families. Of these, 22 (11 for each syndrome) were informative. They found 11 different mutations in the 22 families. By molecular means they proved that the origin of these different mutations was paternal in all informative cases analyzed. Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34.50 +/- 7.65 years vs 30.45 +/- 1.28 years, P less than 0.01). The data extended previous information on advanced paternal age for sporadic FGFR2 mutations causing Apert syndrome and FGFR3 mutations causing achondroplasia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a screening of 14 patients with craniosynostosis syndromes known to be related to FGFR2, <a href="#33" class="mim-tip-reference" title="Hollway, G. E., Suthers, G. K., Haan, E. A., Thompson, E., David, D. J., Gecz, J., Mulley, J. C. <strong>Mutation detection in FGFR2 craniosynostosis syndromes.</strong> Hum. Genet. 99: 251-255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9048930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9048930</a>] [<a href="https://doi.org/10.1007/s004390050348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9048930">Hollway et al. (1997)</a> looked for mutations in exons IIIa and IIIc of FGFR2. They found 9 mutations, 8 of which had previously been reported. One patient with Pfeiffer syndrome was found to have a novel mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9048930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#101" class="mim-tip-reference" title="Tartaglia, M., Valeri, S., Velardi, F., Di Rocco, C., Battaglia, P. A. <strong>Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome.</strong> Hum. Genet. 99: 602-606, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150725</a>] [<a href="https://doi.org/10.1007/s004390050413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150725">Tartaglia et al. (1997)</a> reported a de novo G-to-C transversion in exon IIIa of the FGFR2 gene, detected in a patient with severe Pfeiffer clinical features (<a href="#0019">176943.0019</a>). Missense mutations at codon 290 of FGFR2 had been reported previously in Crouzon syndrome, but not in Pfeiffer syndrome. Codon 290 appears to be a mutation hotspot in the FGFR2 gene. A trp290-to-arg substitution results in classic Crouzon syndrome (<a href="#58" class="mim-tip-reference" title="Meyers, G. A., Day, D., Goldberg, R., Daentl, D. L., Przylepa, K. A., Abrams, L. J., Graham, J. M., Jr., Feingold, M., Moeschler, J. B., Rawnsley, E., Scott, A. F., Jabs, E. W. <strong>FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.</strong> Am. J. Hum. Genet. 58: 491-498, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644708</a>]" pmid="8644708">Meyers et al., 1996</a>), whereas trp290 to gly results in an atypically mild form of Crouzon syndrome (<a href="#71" class="mim-tip-reference" title="Park, W.-J., Meyers, G. A., Li, X., Theda, C., Day, D., Orlow, S. J., Jones, M. C., Jabs, E. W. <strong>Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.</strong> Hum. Molec. Genet. 4: 1229-1233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528214</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528214">Park et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528214+9150725+8644708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#99" class="mim-tip-reference" title="Steinberger, D., Vriend, G., Mulliken, J. B., Muller, U. <strong>The mutations in FGFR2-associated craniosynostoses are clustered in five structural elements of immunoglobulin-like domain III of the receptor.</strong> Hum. Genet. 102: 145-150, 1998. Note: Erratum: Hum. Genet. 102: 495 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521581</a>] [<a href="https://doi.org/10.1007/s004390050668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521581">Steinberger et al. (1998)</a> reviewed the reported FGFR2 mutations associated with craniosynostoses and described 3 previously unrecognized mutations. They pointed out that the known mutations involved 5 distinct structural elements of the receptor. The changes within these elements affect receptor function by various mechanisms, including altered dimerization, truncation, increased mobility between Ig domains, disintegration of IgIII, and alteration of the ligand-binding site. An erratum for the article by <a href="#99" class="mim-tip-reference" title="Steinberger, D., Vriend, G., Mulliken, J. B., Muller, U. <strong>The mutations in FGFR2-associated craniosynostoses are clustered in five structural elements of immunoglobulin-like domain III of the receptor.</strong> Hum. Genet. 102: 145-150, 1998. Note: Erratum: Hum. Genet. 102: 495 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521581</a>] [<a href="https://doi.org/10.1007/s004390050668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521581">Steinberger et al. (1998)</a> included a new Table 2, which listed FGFR2 mutations found in craniosynostoses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Apert syndrome results from specific mutations at 2 adjacent residues of the FGFR2 gene, ser252 to trp (<a href="#0010">176943.0010</a>) and pro253 to arg (<a href="#0011">176943.0011</a>), predicted to lie in the linker region between IgII and IgIII regions of the portions of the FGFR2 ligand-binding domain. <a href="#1" class="mim-tip-reference" title="Anderson, J., Burns, H. D., Enriquez-Harris, P., Wilkie, A. O. M., Heath, J. K. <strong>Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand.</strong> Hum. Molec. Genet. 7: 1475-1483, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700203</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700203">Anderson et al. (1998)</a> analyzed the interaction of FGF ligands with wildtype and Apert-type mutant FGFR2 ectodomains in solution. Wildtype and Apert-type receptors form a complex with FGF ligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics and specificity of ligand binding to wildtype and Apert mutant receptors were analyzed using surface plasmon resonance techniques. <a href="#1" class="mim-tip-reference" title="Anderson, J., Burns, H. D., Enriquez-Harris, P., Wilkie, A. O. M., Heath, J. K. <strong>Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand.</strong> Hum. Molec. Genet. 7: 1475-1483, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700203</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700203">Anderson et al. (1998)</a> found that Apert mutations, compared with wildtype, exhibited a selective decrease in the dissociation kinetics of FGF2, but not of other FGF ligands examined. In contrast, the substitution ser252 to leu in FGFR2, previously observed in several asymptomatic individuals, exhibited wildtype kinetics. These findings indicate that Apert syndrome arises as a result of increased affinity of mutant receptors for specific FGF ligands which leads to activation of signaling under conditions where availability of ligand is limiting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Apert syndrome is commonly accompanied by acne. <a href="#64" class="mim-tip-reference" title="Munro, C. S., Wilkie, A. O. M. <strong>Epidermal mosaicism producing localised acne: somatic mutation in FGFR2.</strong> Lancet 352: 704-705, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9728990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9728990</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)60820-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9728990">Munro and Wilkie (1998)</a>, cognizant of this and with unifying insight, studied a patient who was well except for acne, which was present in the pattern described by Blaschko in the 19th century (<a href="#39" class="mim-tip-reference" title="Jackson, R. <strong>The lines of Blaschko: a review and reconsideration.</strong> Brit. J. Derm. 95: 349-360, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/788770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">788770</a>] [<a href="https://doi.org/10.1111/j.1365-2133.1976.tb00835.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="788770">Jackson, 1976</a>). In this pattern, abnormality of the skin is limited to a linear or whirled pattern. Commonly misinterpreted as dermatomal, the pattern, and therefore the mechanism, is quite distinct. This was interpreted by <a href="#92" class="mim-tip-reference" title="Shuster, S. <strong>Dermatology in Clinical Medicine.</strong> Oxford: Oxford Univ. Press (pub.) 1978."None>Shuster (1978)</a> as representing the clonal pattern of movement of cells during development. <a href="#64" class="mim-tip-reference" title="Munro, C. S., Wilkie, A. O. M. <strong>Epidermal mosaicism producing localised acne: somatic mutation in FGFR2.</strong> Lancet 352: 704-705, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9728990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9728990</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)60820-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9728990">Munro and Wilkie (1998)</a> reasoned that if a germline defect in FGFR2 causes acne in the context of Apert syndrome, a mutation confined to epidermal cells (because it had arisen during development) might produce acne in the pattern described by Blaschko. They showed that one of the common FGFR2 mutations in Apert syndrome, a ser252-to-trp substitution, is present in the abnormal but not the normal skin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=788770+9728990" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Passos-Bueno, M. R., Wilcox, W. R., Jabs, E. W., Sertie, A. L., Alonso, L. G., Kitoh, H. <strong>Clinical spectrum of fibroblast growth factor receptor mutations.</strong> Hum. Mutat. 14: 115-125, 1999. Note: Erratum: Hum. Mutat. 17: 431 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10425034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10425034</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)14:2<115::AID-HUMU3>3.0.CO;2-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10425034">Passos-Bueno et al. (1999)</a> provided an up-to-date listing of the mutations in FGFR1, FGFR2, and FGFR3 associated with distinct clinical entities, including achondroplasia (<a href="/entry/100800">100800</a>), hypochondroplasia (<a href="/entry/146000">146000</a>), platyspondylic lethal skeletal dysplasia (see <a href="/entry/151210">151210</a> and <a href="/entry/187600">187600</a>), thanatophoric dysplasia (see <a href="/entry/187600">187600</a> and <a href="/entry/187601">187601</a>), Antley-Bixler syndrome (<a href="/entry/207410">207410</a>), Apert syndrome (<a href="/entry/101200">101200</a>), Beare-Stevenson cutis gyrata syndrome (BSTVS; <a href="/entry/123790">123790</a>), Crouzon syndrome (<a href="/entry/123500">123500</a>), Jackson-Weiss syndrome (<a href="/entry/123150">123150</a>), Pfeiffer syndrome (<a href="/entry/101600">101600</a>), and Saethre-Chotzen syndrome (<a href="/entry/101400">101400</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10425034" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#119" class="mim-tip-reference" title="Yu, K., Herr, A. B., Waksman, G., Ornitz, D. M. <strong>Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.</strong> Proc. Nat. Acad. Sci. 97: 14536-14541, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11121055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11121055</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11121055[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.26.14536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11121055">Yu et al. (2000)</a> demonstrated that the mutations in 2 adjacent amino acid residues that cause Apert syndrome, S252W (<a href="#0010">176943.0010</a>) and P253R (<a href="#0011">176943.0011</a>), break one of the cardinal rules governing ligand specificity of FGFR2. They are located in the highly conserved region linking Ig-like domains II and III of FGFR2. <a href="#119" class="mim-tip-reference" title="Yu, K., Herr, A. B., Waksman, G., Ornitz, D. M. <strong>Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.</strong> Proc. Nat. Acad. Sci. 97: 14536-14541, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11121055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11121055</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11121055[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.26.14536" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11121055">Yu et al. (2000)</a> showed that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated by the mesenchymally expressed ligands FGF7 (<a href="/entry/148180">148180</a>) or FGF10 (<a href="/entry/602115">602115</a>) and the epithelial splice form of FGFR2 (FGFR2b) to be activated by FGF2 (<a href="/entry/134920">134920</a>), FGF6 (<a href="/entry/134921">134921</a>), and FGF9 (<a href="/entry/600921">600921</a>). The data demonstrated loss of ligand specificity of FGFR2 with retained ligand dependence for receptor activation. The data suggested that the severe phenotypes of Apert syndrome likely result from ectopic ligand-dependent activation of FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11121055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Of 260 cases of Apert syndrome studied by <a href="#69" class="mim-tip-reference" title="Oldridge, M., Zackai, E. H., McDonald-McGinn, D. M., Iseki, S., Morriss-Kay, G. M., Twigg, S. R. F., Johnson, D., Wall, S. A., Jiang, W., Theda, C., Jabs, E. W., Wilkie, A. O. M. <strong>De novo Alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.</strong> Am. J. Hum. Genet. 64: 446-461, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973282</a>] [<a href="https://doi.org/10.1086/302245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973282">Oldridge et al. (1999)</a>, 2 did not have missense mutations in the FGFR2 gene but rather de novo Alu insertions upstream or within exon 9 of FGFR2 (<a href="#0025">176943.0025</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To elucidate the mechanism by which 2 activating mutations in FGFR2, ser252 to trp (<a href="#0010">176943.0010</a>) and pro253 to arg (<a href="#0011">176943.0011</a>), cause Apert syndrome, <a href="#36" class="mim-tip-reference" title="Ibrahimi, O. A., Eliseenkova, A. V., Plotnikov, A. N., Yu, K., Ornitz, D. M., Mohammadi, M. <strong>Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.</strong> Proc. Nat. Acad. Sci. 98: 7182-7187, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11390973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11390973</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11390973[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121183798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11390973">Ibrahimi et al. (2001)</a> determined the crystal structures of these 2 FGFR2 mutants in complex with fibroblast growth factor-2 (FGF2). These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and the sequence alignment of the FGF family, they proposed that the pro253-to-arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the ser252-to-trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of Apert syndrome mutations on FGF binding. The distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among Apert syndrome patients. For example, patients with the ser252-to-trp mutation present more frequently with cleft palate, whereas patients with the pro253-to-arg mutation exhibit more severe syndactyly (<a href="#93" class="mim-tip-reference" title="Slaney, S. F., Oldridge, M., Hurst, J. A., Morriss-Kay, G. M., Hall, C. M., Poole, M. D., Wilkie, A. O. M. <strong>Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.</strong> Am. J. Hum. Genet. 58: 923-932, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651276</a>]" pmid="8651276">Slaney et al., 1996</a>; <a href="#46" class="mim-tip-reference" title="Lajeunie, E., Cameron, R., El Ghouzzi, V., de Parseval, N., Journeau, P., Gonzales, M., Delezoide, A.-L., Bonaventure, J., Le Merrer, M., Renier, D. <strong>Clinical variability in patients with Apert's syndrome.</strong> J. Neurosurg. 90: 443-447, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10067911</a>] [<a href="https://doi.org/10.3171/jns.1999.90.3.0443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10067911">Lajeunie et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10067911+8651276+11390973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Most mutations in Crouzon, Pfeiffer, and Apert syndromes occur in the extracellular third Ig-like domain and adjacent linker regions (exons IIIa and IIIc) of the FGFR2 gene. <a href="#115" class="mim-tip-reference" title="Wong, L.-J. C., Chen, T.-J., Dai, P., Bird, L., Muenke, M. <strong>Novel SNP at the common primer site of exon IIIa of FGFR2 gene causes error in molecular diagnosis of craniosynostosis syndrome.</strong> Am. J. Med. Genet. 102: 282-285, 2001. Note: Erratum: Am. J. Med. Genet. 109: 166 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11484208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11484208</a>] [<a href="https://doi.org/10.1002/ajmg.1461" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11484208">Wong et al. (2001)</a> pointed out that an error in molecular diagnosis of craniosynostosis syndrome can result from a single nucleotide polymorphism (SNP) located in the commonly used primer site. They reported patients who appeared to be homozygous for particular mutations because of this polymorphism, which they determined to have a frequency of 3% in the general population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11484208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study the apparent clustering of mutations in the IgIII region of FGFR2, <a href="#43" class="mim-tip-reference" title="Kan, S., Elanko, N., Johnson, D., Cornejo-Roldan, L., Cook, J., Reich, E. W., Tomkins, S., Verloes, A., Twigg, S. R. F., Rannan-Eliya, S., McDonald-McGinn, D. M., Zackai, E. H., Wall, S. A., Muenke, M., Wilkie, A. O. M. <strong>Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.</strong> Am. J. Hum. Genet. 70: 472-486, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 1258 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781872</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11781872[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/338758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781872">Kan et al. (2002)</a> screened 259 patients with craniosynostosis in whom mutations in other genes, such as FGFR1, FGFR3, and TWIST1 (<a href="/entry/601622">601622</a>), had been excluded. Unbiased estimates of the mutation distribution were permitted because part of the screen was a cohort-based study. Although most of the FGFR2 mutations in the cohort sample (61 of 62) were localized to the IIIa and IIIc exons, <a href="#43" class="mim-tip-reference" title="Kan, S., Elanko, N., Johnson, D., Cornejo-Roldan, L., Cook, J., Reich, E. W., Tomkins, S., Verloes, A., Twigg, S. R. F., Rannan-Eliya, S., McDonald-McGinn, D. M., Zackai, E. H., Wall, S. A., Muenke, M., Wilkie, A. O. M. <strong>Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.</strong> Am. J. Hum. Genet. 70: 472-486, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 1258 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781872</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11781872[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/338758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781872">Kan et al. (2002)</a> identified mutations in 7 additional exons, including 6 distinct mutations in the tyrosine kinase region and a single mutation in the IgII domain. Most of the patients with atypical mutations had diagnoses of Pfeiffer syndrome or Crouzon syndrome. Overall, FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in the prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or sagittal sutures. <a href="#43" class="mim-tip-reference" title="Kan, S., Elanko, N., Johnson, D., Cornejo-Roldan, L., Cook, J., Reich, E. W., Tomkins, S., Verloes, A., Twigg, S. R. F., Rannan-Eliya, S., McDonald-McGinn, D. M., Zackai, E. H., Wall, S. A., Muenke, M., Wilkie, A. O. M. <strong>Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.</strong> Am. J. Hum. Genet. 70: 472-486, 2002. Note: Erratum: Am. J. Hum. Genet. 71: 1258 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781872/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781872</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11781872[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/338758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781872">Kan et al. (2002)</a> concluded that the spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that the IgIIIa/IIIc region represents a genuine mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781872" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an extensive review of the genetics of craniofacial development and malformation, <a href="#111" class="mim-tip-reference" title="Wilkie, A. O. M., Morriss-Kay, G. M. <strong>Genetics of craniofacial development and malformation.</strong> Nature Rev. Genet. 2: 458-468, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11389462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11389462</a>] [<a href="https://doi.org/10.1038/35076601" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11389462">Wilkie and Morriss-Kay (2001)</a> provided a useful diagram of the molecular pathways in cranial suture development with a listing of all craniofacial disorders caused by mutations in the corresponding genes. Four proteins were indicated as having strong evidence for existing in the pathway, with successive downstream targets as follows: TWIST--FGFR2--FGFR1--CBFA1 (<a href="/entry/600211">600211</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11389462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#109" class="mim-tip-reference" title="Warren, S. M., Brunet, L. J., Harland, R. M., Economides, A. N., Longaker, M. T. <strong>The BMP antagonist noggin regulates cranial suture fusion.</strong> Nature 422: 625-629, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12687003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12687003</a>] [<a href="https://doi.org/10.1038/nature01545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12687003">Warren et al. (2003)</a> demonstrated that Noggin (<a href="/entry/602991">602991</a>) is expressed postnatally in the suture mesenchyme of patent, but not of fusing, cranial sutures, and that Noggin expression is suppressed by FGF2 and syndromic FGFR signaling. <a href="#109" class="mim-tip-reference" title="Warren, S. M., Brunet, L. J., Harland, R. M., Economides, A. N., Longaker, M. T. <strong>The BMP antagonist noggin regulates cranial suture fusion.</strong> Nature 422: 625-629, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12687003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12687003</a>] [<a href="https://doi.org/10.1038/nature01545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12687003">Warren et al. (2003)</a> studied the effects of Apert (S252W; <a href="#0010">176943.0010</a>) and Crouzon (see C342Y; <a href="#0001">176943.0001</a>) syndrome Fgfr2 gain-of-function mutations on Noggin production in dural cell and osteoblast cultures. Both Apert and Crouzon syndrome Fgfr2 mutants markedly downregulated Noggin protein production in sagittal dura mater. The Apert and Crouzon Fgfr2 constructs also downregulated Bmp4 (<a href="/entry/112262">112262</a>)-induced Noggin expression in calvarial osteoblasts. Because both Apert and Crouzon syndrome Fgfr gain-of-function mutations promote pathologic suture fusion, <a href="#109" class="mim-tip-reference" title="Warren, S. M., Brunet, L. J., Harland, R. M., Economides, A. N., Longaker, M. T. <strong>The BMP antagonist noggin regulates cranial suture fusion.</strong> Nature 422: 625-629, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12687003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12687003</a>] [<a href="https://doi.org/10.1038/nature01545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12687003">Warren et al. (2003)</a> concluded that their findings provide an important link between the murine models and the gain-of-function Fgfr mutations associated with syndromic Fgfr-mediated craniosynostoses. <a href="#109" class="mim-tip-reference" title="Warren, S. M., Brunet, L. J., Harland, R. M., Economides, A. N., Longaker, M. T. <strong>The BMP antagonist noggin regulates cranial suture fusion.</strong> Nature 422: 625-629, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12687003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12687003</a>] [<a href="https://doi.org/10.1038/nature01545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12687003">Warren et al. (2003)</a> also showed that forced expression of Noggin maintained posterior frontal suture patency in mice. They suggested that since ectopic Noggin expression prevented the fusion of mouse posterior frontal sutures, it is possible that therapeutic Noggin could be exploited to control postnatal skeletal development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12687003" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#120" class="mim-tip-reference" title="Zankl, A., Jaeger, G., Bonafe, L., Boltshauser, E., Superti-Furga, A. <strong>Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome.</strong> Am. J. Med. Genet. 131A: 299-300, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523615</a>] [<a href="https://doi.org/10.1002/ajmg.a.30366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523615">Zankl et al. (2004)</a> noted that mutations in the FGFR2 gene cause a variety of craniosynostosis syndromes, and that most mutations had been found in either exon IIIa or IIIc or in the intronic sequence preceding exon IIIc. Mutations outside this hotspot were uncommon and the few identified mutations demonstrated wide clinical variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with mild features of Crouzon syndrome, <a href="#42" class="mim-tip-reference" title="Kan, R., Twigg, S. R. F., Berg, J., Wang, L., Jin, F., Wilkie, A. O. M. <strong>Expression analysis of an FGFR2 IIIc 5-prime splice site mutation (1084+3A-G).</strong> J. Med. Genet. 41: e108, 2004. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15286168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15286168</a>] [<a href="https://doi.org/10.1136/jmg.2004.018507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15286168">Kan et al. (2004)</a> identified heterozygosity for a splice site mutation in the FGFR2 gene (<a href="#0038">176943.0038</a>). Although both A and G are consensus nucleotides at the +3 position of the 5-prime splice site, oligonucleotide hybridization experiments revealed that the A-G substitution causes a switch to the use of a known cryptic 5-prime splice site (see <a href="#0006">176943.0006</a>) within the upstream exon IIIc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15286168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Itoh, N., Linhardt, R. J., Mohammadi, M. <strong>Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities.</strong> Hum. Molec. Genet. 13: 2313-2324, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15282208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15282208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15282208[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddh235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15282208">Ibrahimi et al. (2004)</a> analyzed the effect of the canonic Apert syndrome mutations (<a href="#0010">176943.0010</a>, <a href="#0011">176943.0011</a>), the D321A Pfeiffer syndrome mutation (<a href="#0039">176943.0039</a>), and the S252L/A315S (<a href="#0028">176943.0028</a>) double mutation on FGFR2 ligand binding affinity and specificity using surface plasmon resonance. Both Apert syndrome mutations and the D321A Pfeiffer syndrome mutation, but not the S252L/A315S double mutation, increased the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. All 4 pathogenic mutations also violated FGFR2c ligand binding specificity and enabled this receptor to bind FGF10. The authors proposed that an increase in mutant FGFR2c binding to multiple FGFs may result in craniosynostosis, whereas binding of mutant FGFR2c to FGF10 may result in severe limb pathology. Structural and biophysical analyses showed that Apert syndrome mutations in FGFR2b also enhanced and violated FGFR2b ligand binding affinity and specificity, respectively. <a href="#37" class="mim-tip-reference" title="Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Itoh, N., Linhardt, R. J., Mohammadi, M. <strong>Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities.</strong> Hum. Molec. Genet. 13: 2313-2324, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15282208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15282208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15282208[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddh235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15282208">Ibrahimi et al. (2004)</a> suggested that elevated Apert syndrome mutant FGFR2b signaling may account for the dermatologic manifestations of Apert syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15282208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="McGillivray, G., Savarirayan, R., Cox, T. C., Stojkoski, C., McNeil, R., Bankier, A., Bateman, J. F., Roscioli, T., Gardner, R. J. M., Lamande, S. R. <strong>Familial scaphocephaly syndrome caused by a novel mutation in the FGFR2 tyrosine kinase domain.</strong> J. Med. Genet. 42: 656-662, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061565</a>] [<a href="https://doi.org/10.1136/jmg.2004.027888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061565">McGillivray et al. (2005)</a> identified a mutation in the FGFR2 gene (<a href="#0034">176943.0034</a>) in a 3-generation family with a form of craniosynostosis characterized by scaphocephaly, maxillary retrusion, and impaired intellectual development (<a href="/entry/609579">609579</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy with scaphocephaly and an Axenfeld-Rieger anomaly, <a href="#54" class="mim-tip-reference" title="McCann, E., Kaye, S. B., Newman, W., Norbury, G., Black, G. C. M., Ellis, I. H. <strong>Novel phenotype of craniosynostosis and ocular anterior chamber dysgenesis with a fibroblast growth factor receptor 2 mutation.</strong> Am. J. Med. Genet. 138A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16158432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16158432</a>] [<a href="https://doi.org/10.1002/ajmg.a.30944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16158432">McCann et al. (2005)</a> identified heterozygosity for an ala344-to-ala mutation in the FGFR2 gene (A344A; <a href="#0006">176943.0006</a>). The authors noted that severe ocular anterior chamber dysgenesis (Peters anomaly) had been previously described in 3 patients with severe craniosynostosis syndromes (see <a href="#0024">176943.0024</a> and <a href="#66" class="mim-tip-reference" title="Okajima, K., Robinson, L. K., Hart, M. A., Abuelo, D. N., Cowan, L. S., Hasegawa, T., Maumenee, I. H., Jabs, E. W. <strong>Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.</strong> Am. J. Med. Genet. 85: 160-170, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10406670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10406670</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990716)85:2<160::aid-ajmg11>3.0.co;2-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10406670">Okajima et al., 1999</a>), and concluded that the FGFR2 gene has a role in anterior chamber embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10406670+16158432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Lajeunie, E., Heuertz, S., El Ghouzzi, V., Martinovic, J., Renier, D., Le Merrer, M., Bonaventure, J. <strong>Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome.</strong> Europ. J. Hum. Genet. 14: 289-298, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16418739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16418739</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16418739">Lajeunie et al. (2006)</a> screened 131 patients with clinical features of Apert, Crouzon, Pfeiffer, or Jackson-Weiss syndromes and identified mutations in FGFR1, FGFR2, or FGFR3 in 125 patients. The authors noted that 2 FGFR2 mutations creating cysteine residues, W290C (<a href="#0019">176943.0019</a>) and Y340C, caused severe forms of Pfeiffer syndrome, whereas conversion of the same residues into another amino acid, W290R/W290G (<a href="#0021">176943.0021</a>/<a href="#0022">176943.0022</a>) or Y340H (<a href="#0004">176943.0004</a>), resulted in the Crouzon phenotype exclusively. <a href="#47" class="mim-tip-reference" title="Lajeunie, E., Heuertz, S., El Ghouzzi, V., Martinovic, J., Renier, D., Le Merrer, M., Bonaventure, J. <strong>Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome.</strong> Europ. J. Hum. Genet. 14: 289-298, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16418739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16418739</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16418739">Lajeunie et al. (2006)</a> concluded that the mutation spectrum of FGFR2 mutations in Crouzon and Pfeiffer syndromes is wider than originally thought, and that despite some overlap, Crouzon and Pfeiffer syndromes are preferentially accounted for by 2 distinct sets of FGFR2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16418739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Autosomal dominant lacrimoauriculodentodigital (LADD) syndrome (LADD1; <a href="/entry/149730">149730</a>) is a multiple congenital anomaly mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments. <a href="#87" class="mim-tip-reference" title="Rohmann, E., Brunner, H. G., Kayserili, H., Uyguner, O., Nurnberg, G., Lew, E. D., Dobbie, A., Eswarakumar, V. P., Uzumcu, A., Ulubil-Emeroglu, M., Leroy, J. G., Li, Y., and 9 others. <strong>Mutations in different components of FGF signaling in LADD syndrome.</strong> Nature Genet. 38: 414-417, 2006. Note: Erratum: Nature Genet. 38: 495 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501574</a>] [<a href="https://doi.org/10.1038/ng1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501574">Rohmann et al. (2006)</a> found mutations in the FGFR2 gene in 3 families and a sporadic case of LADD syndrome. In a Dutch and an English LADD family they found the same heterozygous missense mutation, A648T (<a href="#0035">176943.0035</a>), in affected members. They showed that the mutation probably originated independently in these families, as there was no common founder haplotype. In another family a heterozygous 3-bp deletion was found (<a href="#0036">176943.0036</a>). In a sporadic case of LADD syndrome a de novo missense mutation, A628T (<a href="#0037">176943.0037</a>), was identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16501574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a sperm study of 97 men aged 22 to 80 years, <a href="#116" class="mim-tip-reference" title="Wyrobek, A. J., Eskenazi, B., Young, S., Arnheim, N., Tiemann-Boege, I., Jabs, E. W., Glaser, R. L., Pearson, F. S., Evenson, D. <strong>Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm.</strong> Proc. Nat. Acad. Sci. 103: 9601-9606, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16766665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16766665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16766665[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0506468103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16766665">Wyrobek et al. (2006)</a> found associations between increased age and genomic defects as measured by the DNA fragmentation index and increased age and the FGFR3 1138G-A mutation (<a href="/entry/134934#0001">134934.0001</a>) without evidence for an age threshold. However, there was no association between age and frequency of sperm with immature chromatin, aneuploidies/diploidies, FGFR2 mutations causing Apert syndrome (i.e., <a href="#0010">176943.0010</a>), or sex ratio. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16766665" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#86" class="mim-tip-reference" title="Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C. <strong>Impaired FGF signaling contributes to cleft lip and palate.</strong> Proc. Nat. Acad. Sci. 104: 4512-4517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0607956104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360555">Riley et al. (2007)</a> analyzed 12 genes involved in the fibroblast growth factor signaling pathway in nonsyndromic cleft lip or palate families and identified 7 likely disease-causing mutations in which structural analysis predicted functional impairment in the FGFR1, FGFR2, FGFR3, and FGF8 (<a href="/entry/600483">600483</a>) genes. <a href="#86" class="mim-tip-reference" title="Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C. <strong>Impaired FGF signaling contributes to cleft lip and palate.</strong> Proc. Nat. Acad. Sci. 104: 4512-4517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360555</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360555[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0607956104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360555">Riley et al. (2007)</a> suggested that the FGF signaling pathway may contribute to as much as 3 to 5% of nonsyndromic cleft lip or palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Miraoui, H., Ringe, J., Haupl, T., Marie, P. J. <strong>Increased EFG- and PDGF-alpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis.</strong> Hum. Molec. Genet. 19: 1678-1689, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20124286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20124286</a>] [<a href="https://doi.org/10.1093/hmg/ddq045" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20124286">Miraoui et al. (2010)</a> used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutation in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR (<a href="/entry/131550">131550</a>) and PDGFR-alpha (<a href="/entry/173490">173490</a>) expression was abnormally increased in human Apert calvaria osteoblasts compared with wildtype cells. Pharmacologic inhibition of EGFR and PDGFR reduced the pathologic upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Activated FGFR2 enhanced EGFR and PDGFR-alpha mRNA expression via activation of PKC-alpha (<a href="/entry/176960">176960</a>)-dependent AP1 (see JUN, <a href="/entry/165160">165160</a>) transcriptional activity. The increased EGFR protein expression in Apert osteoblasts resulted in part from a posttranscriptional mechanism involving increased Sprouty2 (<a href="/entry/602466">602466</a>)-Cbl (<a href="/entry/165360">165360</a>) interaction, leading to Cbl sequestration and reduced EGFR ubiquitination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20124286" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Merrill, A. E., Sarukhanov, A., Krejci, P., Idoni, B., Camacho, N., Estrada, K. D., Lyons, K. M., Deixler, H., Robinson, H., Chitayat, D., Curry, C. J., Lachman, R. S., Wilcox, W. R., Krakow, D. <strong>Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.</strong> Am. J. Hum. Genet. 90: 550-557, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22387015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22387015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22387015">Merrill et al. (2012)</a> analyzed 6 candidate genes in 3 female fetuses and 1 male fetus with a perinatal lethal bent bone dysplasia syndrome (BBDS1; <a href="/entry/614592">614592</a>) and identified heterozygosity for the same de novo missense mutation in the FGFR2 gene in 3 of them (M391R; <a href="#0043">176943.0043</a>), with a different heterozygous FGFR2 mutation detected in the remaining fetus (Y381D; <a href="#0044">176943.0044</a>). <a href="#56" class="mim-tip-reference" title="Merrill, A. E., Sarukhanov, A., Krejci, P., Idoni, B., Camacho, N., Estrada, K. D., Lyons, K. M., Deixler, H., Robinson, H., Chitayat, D., Curry, C. J., Lachman, R. S., Wilcox, W. R., Krakow, D. <strong>Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.</strong> Am. J. Hum. Genet. 90: 550-557, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22387015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22387015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22387015">Merrill et al. (2012)</a> stated that the clinical and genetic findings of the 4 affected individuals constituted a distinct disorder that they designated 'bent bone dysplasia (BBD)-FGFR2 type.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22387015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 182 Spanish probands with craniosynostosis, <a href="#75" class="mim-tip-reference" title="Paumard-Hernandez, B., Berges-Soria, J., Barroso, E., Rivera-Pedroza, C. I., Perez-Carrizosa, V., Benito-Sanz, S., Lopez-Messa, E., Santos, F., Garcia-Recuero, I. I., Romance, A., Ballesta-Martinez, M. J., Lopez-Gonzalez, V., Campos-Barros, A., Cruz, J., Guillen-Navarro, E., Sanchez del Pozo, J., Lapunzina, P., Garcia-Minaur, S., Heath, K. E. <strong>Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.</strong> Europ. J. Hum. Genet. 23: 907-914, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25271085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25271085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25271085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25271085">Paumard-Hernandez et al. (2015)</a> screened 5 craniosynostosis-associated genes, including FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 (<a href="/entry/300035">300035</a>). The 2 characteristic Apert syndrome-associated FGFR2 mutations, S252W and P253R, were detected in 23 (85%) of 27 patients with a clinical diagnosis of Apert syndrome. The authors noted that the 4 remaining patients were referred for 'possible' Apert syndrome and likely had a different type of craniosynostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25271085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations</em></strong></p><p>
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<a href="#40" class="mim-tip-reference" title="Jang, J.-H., Shin, K.-H., Park, J.-G. <strong>Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers.</strong> Cancer Res. 61: 3541-3543, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11325814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11325814</a>]" pmid="11325814">Jang et al. (2001)</a> identified a heterozygous somatic mutation in the FGFR2 gene (S267P; <a href="#0029">176943.0029</a>) in gastric cancer tissue (<a href="/entry/137215">137215</a>). The mutation was an activating mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11325814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Pollock, P. M., Gartside, M. G., Dejeza, L. C., Powell, M. A., Mallon, M. A., Cancer Genome Project, Davies, H., Mohammadi, M., Futreal, P. A., Stratton, M. R., Trent, J. M., Goodfellow, P. J. <strong>Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes.</strong> Oncogene 26: 7158-7162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525745</a>] [<a href="https://doi.org/10.1038/sj.onc.1210529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525745">Pollock et al. (2007)</a> identified 11 different somatic FGFR2 mutations (see, e.g., <a href="#0010">176943.0010</a> and <a href="#0015">176943.0015</a>) in 3 (30%) of 10 endometrial cancer (<a href="/entry/608089">608089</a>) cell lines and in 19 (10%) of 187 primary endometrial carcinomas. The majority of the mutations were identical to germline activating mutations that cause skeletal dysplasias. There was no apparent correlation between FGFR2 mutation and overall survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Dutt, A., Salvesen, H. B., Chen, T.-H., Ramos, A. H., Onofrio, R. C., Hatton, C., Nicoletti, R., Winckler, W., Grewal, R., Hanna, M., Wyhs, N., Ziaugra, L., and 13 others. <strong>Drug-sensitive FGFR2 mutations in endometrial carcinoma.</strong> Proc. Nat. Acad. Sci. 105: 8713-8717, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18552176/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18552176</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18552176[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0803379105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18552176">Dutt et al. (2008)</a> found FGFR2 mutations in 15 (12.3%) of 122 primary endometrial carcinomas, as well as in 2 of 42 lung squamous cell carcinomas and in 2 of 46 cervical carcinomas. Many of the mutations were identical to those associated with congenital craniofacial developmental disorders. Ectopic expression of the mutations in mouse fibroblasts demonstrated constitutive activation and oncogenicity, and inhibition of FGFR2 kinase activity in endometrial cell lines bearing such FGFR2 mutations inhibited transformation and survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18552176" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Ota, S., Zhou, Z.-Q., Link, J. M., Hurlin, P. J. <strong>The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects.</strong> Hum. Molec. Genet. 18: 2609-2621, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19403560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19403560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19403560[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19403560">Ota et al. (2009)</a> showed that birth defect and cancer-associated FGFR2 mutants promoted DNA-damage signaling and p53 (<a href="/entry/191170">191170</a>)-dependent senescence in primary mouse and human cells. Senescence promoted by FGFR mutants was associated with downregulation of c-Myc (<a href="/entry/190080">190080</a>) and forced expression of c-Myc facilitated senescence escape. Whereas c-Myc expression facilitated senescence bypass, mutant FGFR2 signaling suppressed c-Myc-dependent apoptosis and led to oncogenic transformation. Cells transformed by coexpression of a constitutively activated FGFR2 mutant plus c-Myc appeared to become highly addicted to FGFR-dependent prosurvival activities, as small molecule inhibition of FGFR signaling resulted in robust p53-dependent apoptosis. <a href="#70" class="mim-tip-reference" title="Ota, S., Zhou, Z.-Q., Link, J. M., Hurlin, P. J. <strong>The role of senescence and prosurvival signaling in controlling the oncogenic activity of FGFR2 mutants associated with cancer and birth defects.</strong> Hum. Molec. Genet. 18: 2609-2621, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19403560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19403560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19403560[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19403560">Ota et al. (2009)</a> suggested that senescence-promoting activities of mutant FGFRs may normally limit their oncogenic potential and may be relevant to their ability to disrupt morphogenesis and cause birth defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19403560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Association with Breast Cancer</em></strong></p><p>
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<a href="#19" class="mim-tip-reference" title="Easton, D. F., Pooley, K. A., Dunning, A. M., Pharoah, P. D. P., Thompson, D., Ballinger, D. G., Struewing, J. P., Morrison, J., Field, H., Luben, R., Wareham, N., Ahmed, S., and 93 others. <strong>Genome-wide association study identifies novel breast cancer susceptibility loci.</strong> Nature 447: 1087-1093, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17529967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17529967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17529967[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17529967">Easton et al. (2007)</a> identified a G/A SNP in intron 2 of the FGFR2 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981582;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981582</a>) that was significantly (p = 2 x 10(-76)) associated with familial breast cancer (<a href="/entry/114480">114480</a>) in a 3-stage genomewide association study of 22,848 cases from 22 studies. <a href="#19" class="mim-tip-reference" title="Easton, D. F., Pooley, K. A., Dunning, A. M., Pharoah, P. D. P., Thompson, D., Ballinger, D. G., Struewing, J. P., Morrison, J., Field, H., Luben, R., Wareham, N., Ahmed, S., and 93 others. <strong>Genome-wide association study identifies novel breast cancer susceptibility loci.</strong> Nature 447: 1087-1093, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17529967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17529967</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17529967[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature05887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17529967">Easton et al. (2007)</a> found that the allele was very common in the U.K. population and thus unlikely to confer increased disease risk individually. However, in combination with other susceptibility alleles, the SNP may become clinically significant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17529967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Hunter, D. J., Kraft, P., Jacobs, K. B., Cox, D. G., Yeager, M., Hankinson, S. E., Wacholder, S., Wang, Z., Welch, R.., Hutchinson, A., Wang, J., Yu, K., and 18 others. <strong>A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.</strong> Nature Genet. 39: 870-874, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17529973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17529973</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17529973[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng2075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17529973">Hunter et al. (2007)</a> identified a SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1219648;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1219648</a>) in intron 2 of the FGFR2 gene that was significantly (p = 1 x 10(-10)) associated with sporadic postmenopausal breast cancer in a 2-stage genomewide association study of 1,145 and 1,776 affected individuals of European ancestry, respectively. The pooled odds ratios were 1.20 for heterozygotes and 1.64 for homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17529973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a sample of 10,358 carriers of BRCA1 (<a href="/entry/113705">113705</a>) or BRCA2 (<a href="/entry/600185">600185</a>) gene mutations from 23 studies, <a href="#3" class="mim-tip-reference" title="Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., and 80 others. <strong>Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.</strong> Am. J. Hum. Genet. 82: 937-948, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18355772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18355772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18355772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.02.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18355772">Antoniou et al. (2008)</a> observed a significant association between breast cancer and the minor allele of G/A SNP in intron 2 (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981582;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981582</a>; hazard ratio of 1.32; p-trend = 1.7 x 10(-8)) in BRCA2 carriers, but not in BRCA1 carriers. The authors concluded that this locus interacts multiplicatively on breast cancer risk in BRCA2 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18355772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#104" class="mim-tip-reference" title="Udler, M. S., Meyer, K. B., Pooley, K. A., Karlins, E., Struewing, J. P., Zhang, J., Doody, D. R., MacArthur, S., Tyrer, J., Pharoah, P. D., Luben, R., SEARCH Collaborators, and 23 others. <strong>FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation.</strong> Hum. Molec. Genet. 18: 1692-1703, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19223389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19223389</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19223389[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19223389">Udler et al. (2009)</a> evaluated 8 candidate-causal FGFR2 SNPs in 1,253 African American invasive breast cancer cases and 1,245 controls. A significant association with breast cancer risk was found with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981578;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981578</a> (unadjusted per-allele odds ratio = 1.2, P-trend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. Genotype data from the African American studies were analyzed jointly with data from European (7,196 cases and 7,275 controls) and Asian (3,901 cases and 3,205 controls) studies. In the combined analysis, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981578;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981578</a> was the most strongly associated. Analysis of DNase I hypersensitive sites indicated that only 2 of these mapped to highly accessible chromatin, one of which, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981578;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981578</a>, had previously been implicated in upregulating FGFR2 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19223389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., Prathalingham, R., Dennis, J., Bolla, M. K., Wang, Q., de Santiago, I., Hopper, J. L., and 191 others. <strong>Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.</strong> Am. J. Hum. Genet. 93: 1046-1060, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24290378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24290378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24290378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.10.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24290378">Meyer et al. (2013)</a> conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. <a href="#57" class="mim-tip-reference" title="Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., Prathalingham, R., Dennis, J., Bolla, M. K., Wang, Q., de Santiago, I., Hopper, J. L., and 191 others. <strong>Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.</strong> Am. J. Hum. Genet. 93: 1046-1060, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24290378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24290378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24290378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.10.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24290378">Meyer et al. (2013)</a> identified 3 statistically independent risk signals within the 10q26 FGFR2 locus. Within risk signals 1 and 3, genetic analysis identified 5 and 2 variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and EMSA to study protein-DNA binding, <a href="#57" class="mim-tip-reference" title="Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., Prathalingham, R., Dennis, J., Bolla, M. K., Wang, Q., de Santiago, I., Hopper, J. L., and 191 others. <strong>Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.</strong> Am. J. Hum. Genet. 93: 1046-1060, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24290378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24290378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24290378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.10.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24290378">Meyer et al. (2013)</a> identified <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35054928;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs35054928</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981578;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981578</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45631563;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs45631563</a> as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 (<a href="/entry/602294">602294</a>) preferentially bound to the risk-associated allele (C) of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2981578;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2981578</a> and was able to recruit estrogen receptor-alpha (<a href="/entry/133430">133430</a>) to this site in an allele-specific manner, whereas E2F1 (<a href="/entry/189971">189971</a>) preferentially bound the risk variant of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs35054928;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs35054928</a>. The risk alleles were preferentially found in open chromatin and bound by Ser5-phosphorylated RNA polymerase II (see <a href="/entry/180660">180660</a>), suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region <a href="#57" class="mim-tip-reference" title="Meyer, K. B., O'Reilly, M., Michailidou, K., Carlebur, S., Edwards, S. L., French, J. D., Prathalingham, R., Dennis, J., Bolla, M. K., Wang, Q., de Santiago, I., Hopper, J. L., and 191 others. <strong>Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.</strong> Am. J. Hum. Genet. 93: 1046-1060, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24290378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24290378</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24290378[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.10.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24290378">Meyer et al. (2013)</a> concluded that a role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen receptor-positive disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24290378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K., Lonai, P. <strong>Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development.</strong> Proc. Nat. Acad. Sci. 95: 5082-5087, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9560232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9560232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9560232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.9.5082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9560232">Arman et al. (1998)</a> found that disruption of the FGFR2 gene in mice resulted in a recessive embryonic lethal mutation. Preimplantation development was normal until the blastocyst stage. Homozygous mutant embryos died a few hours after implantation at a random position in the uterine crypt, with collapsed yolk cavity. Other observations indicated that FGFR2 is required for early postimplantation development between implantation and the formation of the egg cylinder. <a href="#4" class="mim-tip-reference" title="Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K., Lonai, P. <strong>Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development.</strong> Proc. Nat. Acad. Sci. 95: 5082-5087, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9560232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9560232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9560232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.9.5082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9560232">Arman et al. (1998)</a> suggested that FGFR2 contributes to the outgrowth, differentiation, and maintenance of the inner cell mass and raised the possibility that this activity is mediated by FGF4 (<a href="/entry/164980">164980</a>) signals transmitted by FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9560232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Deng, C., Bedford, M., Li, C., Xu, X., Yang, X., Dunmore, J., Leder, P. <strong>Fibroblast growth factor receptor-1 (FGFR-1) is essential for normal neural tube and limb development.</strong> Dev. Biol. 185: 42-54, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9169049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9169049</a>] [<a href="https://doi.org/10.1006/dbio.1997.8553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9169049">Deng et al. (1997)</a> showed by chimera experiments with homozygous mutant embryonic stem (ES) cells that Fgfr1 has a role in limb and central nervous system development. Involvement of Fgfr2 in limb outgrowth was indicated by a targeted mutation that displayed no limb buds but, because of placental insufficiency, did not survive beyond early limb outgrowth (<a href="#117" class="mim-tip-reference" title="Xu, X., Weinstein, M., Li, C., Naski, M., Cohen, R. I., Ornitz, D. M., Leder, P., Deng, C. <strong>Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction.</strong> Development 125: 753-765, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435295</a>] [<a href="https://doi.org/10.1242/dev.125.4.753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435295">Xu et al., 1998</a>). Fgfr2 in the early embryo is expressed in the trophectoderm, and this extra-embryonic localization persists into mid- and late gestation, when Fgfr2 is also expressed in multiple developing organs. To gain insight into the later functions of Fgfr2, <a href="#5" class="mim-tip-reference" title="Arman, E., Haffner-Krausz, R., Gorivodsky, M., Lonai, P. <strong>Fgfr2 is required for limb outgrowth and lung-branching morphogenesis.</strong> Proc. Nat. Acad. Sci. 96: 11895-11899, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518547</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10518547[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.21.11895" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10518547">Arman et al. (1999)</a> constructed fusion chimeras from homozygous mutant embryonic stem cells and wildtype tetraploid embryos. This allowed survival until term and revealed that Fgfr2 is required for both limb outgrowth and branching lung morphogenesis. The use of fusion chimeras demonstrated that early lethality was indeed because of trophectoderm defects and indicated that in the embryonic cell lineages Fgfr2 activity manifests in limb and lung development. Highly similar lung and limb phenotypes were detected in a loss-of-function mutation of Fgf10 (<a href="/entry/602115">602115</a>), a ligand of Fgfr2. It is likely, therefore, that whereas during early development Fgfr2 interacts with Fgf4, interactions between Fgf10 and Fgfr2 may be required in limb and lung development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9435295+9169049+10518547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In Fgf10 -/-, Fgfr2b -/-, and Sonic hedgehog (SHH; <a href="/entry/600725">600725</a>) -/- mice, which all exhibit cleft palate, <a href="#85" class="mim-tip-reference" title="Rice, R., Spencer-Dene, B., Connor, E. C., Gritli-Linde, A., McMahon, A. P., Dickson, C., Thesleff, I., Rice, D. P. C. <strong>Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.</strong> J. Clin. Invest. 113: 1692-1700, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199404</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199404[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI20384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199404">Rice et al. (2004)</a> showed that Shh is a downstream target of Fgf10/Fgfr2b signaling. Using BrdU staining, they demonstrated that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by the finding that cell proliferation was decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b -/- mice. <a href="#85" class="mim-tip-reference" title="Rice, R., Spencer-Dene, B., Connor, E. C., Gritli-Linde, A., McMahon, A. P., Dickson, C., Thesleff, I., Rice, D. P. C. <strong>Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.</strong> J. Clin. Invest. 113: 1692-1700, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15199404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15199404</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15199404[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI20384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15199404">Rice et al. (2004)</a> concluded that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an FGF-SHH signaling network. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15199404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mice deficient for fibroblast growth factor receptors show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, and profound defects in membranous and endochondral bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. <a href="#32" class="mim-tip-reference" title="Hajihosseini, M. K., Wilson, S., De Moerlooze, L., Dickson, C. <strong>A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes.</strong> Proc. Nat. Acad. Sci. 98: 3855-3860, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11274405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11274405</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11274405[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.071586898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11274405">Hajihosseini et al. (2001)</a> showed that heterozygotic abrogation of exon 9 of the Fgfr2 gene in mice caused a splicing switch resulting in a gain-of-function mutation. The consequences were neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. The phenotype was considered to have strong parallels to some Apert (<a href="/entry/101200">101200</a>) and Pfeiffer (<a href="/entry/101600">101600</a>) syndrome patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11274405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Eswarakumar, V. P., Horowitz, M. C., Locklin, R., Morriss-Kay, G. M., Lonai, P. <strong>A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis.</strong> Proc. Nat. Acad. Sci. 101: 12555-12560, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15316116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15316116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15316116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405031101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15316116">Eswarakumar et al. (2004)</a> created transgenic mice expressing a gain-of-function mutation (C342Y; <a href="#0001">176943.0001</a>) in the Fgfr2 gene. Heterozygous mutant mice were viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 (<a href="/entry/166490">166490</a>) expression in the calvaria. Homozygous mutants displayed multiple joint fusions, cleft palate, and trachea and lung defects, and died shortly after birth. They showed enhanced Cbfa1 expression without significant change in chondrocyte-specific gene expression. Histomorphometric analysis and bone marrow stromal cell culture showed a significant increase of osteoblast progenitors with no change in osteoclastogenic cells. Chondrocyte proliferation was decreased in the skull base at embryonic day 14.5 but not later. <a href="#20" class="mim-tip-reference" title="Eswarakumar, V. P., Horowitz, M. C., Locklin, R., Morriss-Kay, G. M., Lonai, P. <strong>A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis.</strong> Proc. Nat. Acad. Sci. 101: 12555-12560, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15316116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15316116</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15316116[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405031101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15316116">Eswarakumar et al. (2004)</a> concluded that the mutant phenotype, including craniosynostosis, is related to FGFR2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of FGFR2c with FGFR3 (<a href="/entry/134934">134934</a>) in the formation of the cartilage model for endochondral bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15316116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Eswarakumar, V. P., Ozcan, F., Lew, E. D., Bae, J. H., Tome, F., Booth, C. J., Adams, D. J., Lax, I., Schlessinger, J. <strong>Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis.</strong> Proc. Nat. Acad. Sci. 103: 18603-18608, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17132737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17132737</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17132737[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609157103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17132737">Eswarakumar et al. (2006)</a> generated C342Y +/- mice and observed ocular proptosis, a rounded cranium, fusion of the coronal sutures, and a significantly shortened facial region in the mutant mice. Expression of the C342Y mutation in cis with L424A and R426A mutations of the juxtamembrane domain resulted in attenuation of signaling pathways by selectively uncoupling Frs2a (<a href="/entry/607743">607743</a>) and activated Fgfr2c, thus preventing premature fusion of sutures and resulting in normal skull development. <a href="#21" class="mim-tip-reference" title="Eswarakumar, V. P., Ozcan, F., Lew, E. D., Bae, J. H., Tome, F., Booth, C. J., Adams, D. J., Lax, I., Schlessinger, J. <strong>Attenuation of signaling pathways stimulated by pathologically activated FGF-receptor 2 mutants prevents craniosynostosis.</strong> Proc. Nat. Acad. Sci. 103: 18603-18608, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17132737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17132737</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17132737[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609157103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17132737">Eswarakumar et al. (2006)</a> also demonstrated that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevented premature fusion of sutures without adversely affecting the development of the skull. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17132737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#91" class="mim-tip-reference" title="Shukla, V., Coumoul, X., Wang, R.-H., Kim, H.-S., Deng, C.-X. <strong>RNA interference and inhibition of MER-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis.</strong> Nature Genet. 39: 1145-1150, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17694057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17694057</a>] [<a href="https://doi.org/10.1038/ng2096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17694057">Shukla et al. (2007)</a> developed mice with conditional expression of Fgfr2 with the S252W (<a href="#0010">176943.0010</a>) missense mutation. Mice carrying the activated form of Fgfr2-S252W showed malformations mimicking the abnormalities found in individuals with Apert syndrome, including dome-shaped skull, widely spaced eyes, premature closure of the coronal suture, and underdeveloped midface. However, coexpression of a small hairpin RNA targeting Fgfr2-S252W completely prevented these malformations and restored normal Fgfr2 signaling as shown by normal levels of Erk1 (<a href="/entry/601795">601795</a>)/Erk2 (<a href="/entry/176948">176948</a>) phosphorylation and reduced expression of Erk1 target genes. Furthermore, treatment of pregnant mice with a pharmacologic inhibitor of Mek1 (<a href="/entry/176872">176872</a>)/Mek2 (<a href="/entry/601263">601263</a>) blocked the phosphorylation and activation of Erk1/Erk2 and resulted in the recovery of Fgfr2-S252W mutant pups that were indistinguishable from wildtype. <a href="#91" class="mim-tip-reference" title="Shukla, V., Coumoul, X., Wang, R.-H., Kim, H.-S., Deng, C.-X. <strong>RNA interference and inhibition of MER-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis.</strong> Nature Genet. 39: 1145-1150, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17694057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17694057</a>] [<a href="https://doi.org/10.1038/ng2096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17694057">Shukla et al. (2007)</a> concluded that ERK activation has a pathogenic role in the craniosynostosis resulting from the S252W substitution in FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17694057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Targeted mutagenesis of Fgf9 (<a href="/entry/600921">600921</a>) in mice causes male-to-female sex reversal. <a href="#45" class="mim-tip-reference" title="Kim, Y., Bingham, N., Sekido, R., Parker, K. L., Lovell-Badge, R., Capel, B. <strong>Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination.</strong> Proc. Nat. Acad. Sci. 104: 16558-16563, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17940049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17940049</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17940049[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0702581104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17940049">Kim et al. (2007)</a> found that targeted Fgfr2 deletion in mouse testis phenocopied Fgf9 knockout, suggesting that Fgfr2 is the Fgf9 receptor in mouse testis. The authors concluded that FGFR2 plays an essential role in testis determination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17940049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Bagheri-Fam, S., Ono, M., Li, L., Zhao, L., Ryan, J., Lai, R., Katsura, Y., Rossello, F. J., Koopman, P., Scherer, G., Bartsch, O., Eswarakumar, J. V. P., Harley, V. R. <strong>FGFR2 mutation in 46,XY sex reversal with craniosynostosis.</strong> Hum. Molec. Genet. 24: 6699-6710, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddv374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362256">Bagheri-Fam et al. (2015)</a> studied the knockin Crouzon mouse model Fgfr2c(C342Y/C342Y) and observed partial male-to-female gonadal sex reversal, characterized by gonads that developed as ovotestes (containing both testicular and ovarian tissue). XY Fgfr2c(C342Y/-) ovaries showed reduced expression of Sertoli cell markers and FGF-responsive genes as well as increased expression of granulosa cell markers, compared to heterozygous XY Fgfr2c +/- knockout testes. In addition, the expression changes in XY Fgfr2c(C342Y/-) ovaries were restored to XY wildtype levels by the addition of the wildtype allele found in the heterozygous Crouzon model, supporting the C342Y mutant receptor showing loss-of-function activity in the gonads. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>44 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176943[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918487 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918487;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014173 OR RCV000014174 OR RCV000547490 OR RCV000762801 OR RCV001090933 OR RCV001196204 OR RCV001730471 OR RCV004795406" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014173, RCV000014174, RCV000547490, RCV000762801, RCV001090933, RCV001196204, RCV001730471, RCV004795406" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014173...</a>
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<p>In 3 unrelated individuals with Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found a G-to-A transition at nucleotide 1037 in the B exon of the FGFR2 gene. This was predicted to result in a cys342-to-tyr (C342Y) substitution within the third Ig domain. The same mutation was found by <a href="#88" class="mim-tip-reference" title="Rutland, P., Pulleyn, L. J., Reardon, W., Baraitser, M., Hayward, R., Jones, B., Malcolm, S., Winter, R. M., Oldridge, M., Slaney, S. F., Poole, M. D., Wilkie, A. O. M. <strong>Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.</strong> Nature Genet. 9: 173-176, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719345</a>] [<a href="https://doi.org/10.1038/ng0295-173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719345">Rutland et al. (1995)</a> in a patient with Pfeiffer syndrome (<a href="/entry/101600">101600</a>), not Crouzon syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7719345+7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Steinberger, D., Mulliken, J. B., Muller, U. <strong>Predisposition for cysteine substitutions in the immunoglobulin-like chain of FGFR2 in Crouzon syndrome.</strong> Hum. Genet. 96: 113-115, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607643</a>] [<a href="https://doi.org/10.1007/BF00214198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607643">Steinberger et al. (1995)</a> found mutations at codon 342 in 3 sporadic cases of Crouzon syndrome. Two of them were G-to-A transitions at position 1037, the mutation described by <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a>. The third was a C-to-G transversion at position 1038, resulting in replacement of cysteine by tryptophan (<a href="#0013">176943.0013</a>). <a href="#96" class="mim-tip-reference" title="Steinberger, D., Mulliken, J. B., Muller, U. <strong>Predisposition for cysteine substitutions in the immunoglobulin-like chain of FGFR2 in Crouzon syndrome.</strong> Hum. Genet. 96: 113-115, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607643</a>] [<a href="https://doi.org/10.1007/BF00214198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607643">Steinberger et al. (1995)</a> pointed out that a mutation in codon 342 had been found in 8 out of 17 cases of Crouzon syndrome and that in 9 cases the mutation occurred at 5 other positions, suggesting that codon 342 of exon B of the FGFR2 gene may be disposed to mutations in Crouzon syndrome. The substitutions of cysteine that appeared to be leading causes of Crouzon syndrome occur in the immunoglobulin-like domain of FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7607643+7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918488;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014177 OR RCV000014178 OR RCV000014179 OR RCV000014180 OR RCV000534888 OR RCV001723565" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014177, RCV000014178, RCV000014179, RCV000014180, RCV000534888, RCV001723565" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014177...</a>
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<p>In a sporadic case of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg (C342R) substitution in the FGFR2 protein. The mutation created a new restriction site which was not found in the clinically normal parents of this patient. The same mutation was found in 5 patients with Pfeiffer syndrome (<a href="/entry/101600">101600</a>), not Crouzon syndrome, by <a href="#88" class="mim-tip-reference" title="Rutland, P., Pulleyn, L. J., Reardon, W., Baraitser, M., Hayward, R., Jones, B., Malcolm, S., Winter, R. M., Oldridge, M., Slaney, S. F., Poole, M. D., Wilkie, A. O. M. <strong>Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.</strong> Nature Genet. 9: 173-176, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719345</a>] [<a href="https://doi.org/10.1038/ng0295-173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719345">Rutland et al. (1995)</a>. As a possible explanation, they pointed to the occurrence of 2 different phenotypes from the asp178-to-asn substitution in the prion protein gene, depending on the amino acid present at position 129 in the product of the same allele. The same mutation was found by <a href="#71" class="mim-tip-reference" title="Park, W.-J., Meyers, G. A., Li, X., Theda, C., Day, D., Orlow, S. J., Jones, M. C., Jabs, E. W. <strong>Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.</strong> Hum. Molec. Genet. 4: 1229-1233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528214</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528214">Park et al. (1995)</a> in a sporadic case of Jackson-Weiss syndrome (<a href="/entry/123150">123150</a>). The patient showed corneal synostosis, hypertelorism with ocular proptosis, midface hypoplasia, deviated nasal septum, obligatory mouthbreathing, moderate hearing deficit with hypoplastic ear canals, wide great toes with medial deviation, and tarsal-metatarsal coalescence (calcaneocuboidal fusions and right fusion of the navicular and first cuneiform bones). No hand anomalies were present by clinical or radiographic examination. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7719345+8528214+7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Antley-Bixler syndrome (ABS2; <a href="/entry/207410">207410</a>), <a href="#83" class="mim-tip-reference" title="Reardon, W., Smith, A., Honour, J. W., Hindmarsh, P., Das, D., Rumsby, G., Nelson, I., Malcolm, S., Ades, L., Sillence, D., Kumar, D., DeLozier-Blanchet, C., McKee, S., Kelly, T., McKeehan, W. L., Baraitser, M., Winter, R. M. <strong>Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?</strong> J. Med. Genet. 37: 26-32, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10633130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10633130</a>] [<a href="https://doi.org/10.1136/jmg.37.1.26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10633130">Reardon et al. (2000)</a> identified the C342R substitution in the FGFR2 gene. The patient had normal male genitalia and a normal steroid profile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10633130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918488;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014181 OR RCV000014182 OR RCV000014183 OR RCV000415484 OR RCV000490034 OR RCV000655416" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014181, RCV000014182, RCV000014183, RCV000415484, RCV000490034, RCV000655416" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014181...</a>
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<p>In a sporadic case of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found a T-to-A transversion at nucleotide 1036 (the same as that involved in the cys342-to-arg mutation), predicting substitution of serine for cysteine (C342S). This mutation created a new restriction site which was not found in the unaffected parents. This same mutation was found in Jackson-Weiss syndrome (<a href="/entry/123150">123150</a>) by <a href="#100" class="mim-tip-reference" title="Tartaglia, M., Di Rocco, C., Lajeunie, E., Valeri, S., Velardi, F., Battaglia, P. A. <strong>Jackson-Weiss syndrome: identification of two novel FGFR2 missense mutations shared with Crouzon and Pfeiffer craniosynostotic disorders.</strong> Hum. Genet. 101: 47-50, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9385368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9385368</a>] [<a href="https://doi.org/10.1007/s004390050584" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9385368">Tartaglia et al. (1997)</a>. The molecular basis for the phenotypic heterogeneity in the face of apparent genetic homogeneity is unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9385368+7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with an 'extreme' Antley-Bixler phenotype (ABS2; <a href="/entry/207410">207410</a>), <a href="#83" class="mim-tip-reference" title="Reardon, W., Smith, A., Honour, J. W., Hindmarsh, P., Das, D., Rumsby, G., Nelson, I., Malcolm, S., Ades, L., Sillence, D., Kumar, D., DeLozier-Blanchet, C., McKee, S., Kelly, T., McKeehan, W. L., Baraitser, M., Winter, R. M. <strong>Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?</strong> J. Med. Genet. 37: 26-32, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10633130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10633130</a>] [<a href="https://doi.org/10.1136/jmg.37.1.26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10633130">Reardon et al. (2000)</a> identified the C342S substitution in the FGFR2 gene. The patient had normal female genitalia and a normal steroid profile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10633130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 15-year-old girl with Crouzon-like craniosynostosis and 46,XY complete gonadal dysgenesis, <a href="#7" class="mim-tip-reference" title="Bagheri-Fam, S., Ono, M., Li, L., Zhao, L., Ryan, J., Lai, R., Katsura, Y., Rossello, F. J., Koopman, P., Scherer, G., Bartsch, O., Eswarakumar, J. V. P., Harley, V. R. <strong>FGFR2 mutation in 46,XY sex reversal with craniosynostosis.</strong> Hum. Molec. Genet. 24: 6699-6710, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddv374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362256">Bagheri-Fam et al. (2015)</a> sequenced the candidate gene FGFR2 and identified heterozygosity for the C342S mutation. DNA from her parents was unavailable for study. Whole-exome sequencing to search for potential modifier variants influencing the proband's phenotype revealed single-nucleotide variants or indels in 193 genes. <a href="#7" class="mim-tip-reference" title="Bagheri-Fam, S., Ono, M., Li, L., Zhao, L., Ryan, J., Lai, R., Katsura, Y., Rossello, F. J., Koopman, P., Scherer, G., Bartsch, O., Eswarakumar, J. V. P., Harley, V. R. <strong>FGFR2 mutation in 46,XY sex reversal with craniosynostosis.</strong> Hum. Molec. Genet. 24: 6699-6710, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddv374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26362256">Bagheri-Fam et al. (2015)</a> noted that although none of the changes were located in 63 genes associated with disorders of sex development, the patient did carry novel changes or indels in 35 genes that in mice are expressed in pre-Sertoli cells at the time of sex determination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918489 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918489;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014175 OR RCV001214882 OR RCV001723564" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014175, RCV001214882, RCV001723564" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014175...</a>
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<p>In a family with Crouzon syndrome (<a href="/entry/123500">123500</a>) in 5 generations, <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found that affected members had a T-to-C transition at nucleotide 1030 predicted to cause a tyr340-to-his amino acid substitution in the gene product. All affected members of the family had the mutation; all unaffected members had the wildtype sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918490 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918490;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014176 OR RCV000623131 OR RCV000655419 OR RCV001565300 OR RCV002287333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014176, RCV000623131, RCV000655419, RCV001565300, RCV002287333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014176...</a>
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<p>In a sporadic case of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found a C-to-G transversion in nucleotide 1073, predicted to cause a ser354-to-cys amino acid change in the gene product. His parents had normal wildtype sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918491 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918491;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918491?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014184 OR RCV000014185 OR RCV000014186 OR RCV000192353 OR RCV000686210 OR RCV000762800 OR RCV001579726 OR RCV002247335 OR RCV002250460 OR RCV002280092 OR RCV002482864" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014184, RCV000014185, RCV000014186, RCV000192353, RCV000686210, RCV000762800, RCV001579726, RCV002247335, RCV002250460, RCV002280092, RCV002482864" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014184...</a>
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<p>On sequencing 2 individuals both from pedigrees with classic features of Crouzon syndrome (<a href="/entry/123500">123500</a>) and autosomal dominant transmission, <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> found a G-to-A transition at nucleotide 1044. This mutation would not result in an amino acid change as it involved the third base of an alanine codon, which raised the possibility that the particular change was simply a polymorphic variant. However, the same SSCP change was not found in any unaffected individual. <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> raised the possibility that the change of the codon from GCG to GCA created a cryptic splice site within the exon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the large Turkish family described by <a href="#98" class="mim-tip-reference" title="Steinberger, D., Reinhartz, T., Unsold, R., Muller, U. <strong>FGFR2 mutation in clinically nonclassifiable autosomal dominant craniosynostosis with pronounced phenotypic variation.</strong> Am. J. Med. Genet. 66: 81-86, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8957519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8957519</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961202)66:1<81::AID-AJMG19>3.0.CO;2-M" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8957519">Steinberger et al. (1996)</a>, the phenotype of craniosynostosis varied greatly. Several persons with the mutation were healthy and had only mild facial findings such as slight hypertelorism and maxillary hypoplasia. Others were severely affected and their craniosynostoses caused increased intracranial pressure with complications such as severe headache and optic nerve compression. The pattern of premature cranial suture closure varied among the patients. Different timing and location of abnormal suture development resulted in phenotypic extremes such as dolichocephaly in 1 patient and brachycephaly in another. Only 1 patient in this family had broad great toes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8957519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a boy with scaphocephaly and an Axenfeld-Rieger anomaly, <a href="#54" class="mim-tip-reference" title="McCann, E., Kaye, S. B., Newman, W., Norbury, G., Black, G. C. M., Ellis, I. H. <strong>Novel phenotype of craniosynostosis and ocular anterior chamber dysgenesis with a fibroblast growth factor receptor 2 mutation.</strong> Am. J. Med. Genet. 138A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16158432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16158432</a>] [<a href="https://doi.org/10.1002/ajmg.a.30944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16158432">McCann et al. (2005)</a> identified heterozygosity for the ala344-to-ala (A344A) mutation in the FGFR2 gene. The boy had no other dysmorphic features, and development was age appropriate; at age 6 years, he had no learning difficulties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16158432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RNA from a patient with Crouzon syndrome in whom <a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> had identified the A344A mutation, <a href="#50" class="mim-tip-reference" title="Li, X., Park, W.-J., Pyeritz, R. E., Jabs, E. W. <strong>Effect on splicing of a silent FGFR2 mutation on Crouzon syndrome. (Letter)</strong> Nature Genet. 9: 232-233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7773284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7773284</a>] [<a href="https://doi.org/10.1038/ng0395-232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7773284">Li et al. (1995)</a> demonstrated that the variant creates a new donor splice site, which results in a stable transcript and an altered receptor with a deletion in the Ig IIIc domain of FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7773284+7874170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918492 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918492;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014187 OR RCV000014188 OR RCV001851846 OR RCV003313919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014187, RCV000014188, RCV001851846, RCV003313919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014187...</a>
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<p><a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> were prompted to examine the FGFR2 gene in the original Amish family with Jackson-Weiss syndrome (<a href="/entry/123150">123150</a>) because the clinical phenotype mapped to the same region, 10q25-q26, as FGFR2. They identified an ala344-to-gly mutation which resulted in a change just 2 residues away from the cysteine involved in the disulfide bond of the third immunoglobulin domain which dictates the ligand-binding specificity of FGFR2. The most distinctive and consistent feature of Jackson-Weiss syndrome is the abnormality of the feet: broad great toes with medial deviation and tarsal-metatarsal coalescence. When the classic manifestations of Crouzon syndrome (shallow orbits with ocular proptosis; <a href="/entry/123500">123500</a>) are present in Jackson-Weiss syndrome, they are usually mild; Crouzon syndrome shows less variability of craniofacial abnormalities and no limb anomalies. The findings of <a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> and <a href="#84" class="mim-tip-reference" title="Reardon, W., Winter, R. M., Rutland, P., Pulleyn, L. J., Jones, B. M., Malcolm, S. <strong>Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.</strong> Nature Genet. 8: 98-103, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987400/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987400</a>] [<a href="https://doi.org/10.1038/ng0994-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987400">Reardon et al. (1994)</a> in these 2 craniosynostosis syndromes indicate the variability in manifestations of mutations in the same gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874170+7987400" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>(<a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> inadvertently cited the ala344-to-gly mutation as arg344-to-gly in one place and as ala342-to-gly in another place. The error was carried over into the table that accompanied the review by <a href="#63" class="mim-tip-reference" title="Mulvihill, J. J. <strong>Craniofacial syndromes: no such thing as a single gene disease.</strong> Nature Genet. 9: 101-103, 1995. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719329</a>] [<a href="https://doi.org/10.1038/ng0295-101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719329">Mulvihill (1995)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874170+7719329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Gorry, M. C., Preston, R. A., White, G. J., Zhang, Y., Singhal, V. K., Losken, H. W., Parker, M. G., Nwokoro, N. A., Post, J. C., Ehrlich, G. D. <strong>Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome.</strong> Hum. Molec. Genet. 4: 1387-1390, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581378</a>] [<a href="https://doi.org/10.1093/hmg/4.8.1387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581378">Gorry et al. (1995)</a> found the ala344-to-gly mutation resulting from a C-to-G transversion at nucleotide 1043 of their FGFR2 clone in a patient with Crouzon syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 CROUZON SYNDROME</strong>
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FGFR2, TYR328CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918493 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918493;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014189 OR RCV000798719 OR RCV004700231" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014189, RCV000798719, RCV004700231" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014189...</a>
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<p>In a familial case of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> identified a tyr328-to-cys mutation in the immunoglobulin domain. In this domain, a third cysteine may perturb the normal secondary loop structure that is created by the normal disulfide bond. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918494;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014190 OR RCV000626619 OR RCV000655421 OR RCV000726654 OR RCV001823713 OR RCV004813038" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014190, RCV000626619, RCV000655421, RCV000726654, RCV001823713, RCV004813038" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014190...</a>
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<p>In a sporadic case of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#38" class="mim-tip-reference" title="Jabs, E. W., Li, X., Scott, A. F., Meyers, G., Chen, W., Eccles, M., Mao, J., Charnas, L. R., Jackson, C. E., Jaye, M. <strong>Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.</strong> Nature Genet. 8: 275-279, 1994. Note: Erratum: Nature Genet. 9: 451 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874170</a>] [<a href="https://doi.org/10.1038/ng1194-275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874170">Jabs et al. (1994)</a> described a ser347-to-cys mutation. The introduction of a third cysteine in the immunoglobulin domain may perturb the normal secondary loop structure that is created by the normal disulfide bond. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs79184941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs79184941;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs79184941?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs79184941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs79184941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014191 OR RCV000014192 OR RCV000263144 OR RCV000552015 OR RCV002476961 OR RCV004527288 OR RCV004532334 OR RCV004795407" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014191, RCV000014192, RCV000263144, RCV000552015, RCV002476961, RCV004527288, RCV004532334, RCV004795407" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014191...</a>
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<p><strong><em>Apert Syndrome</em></strong></p><p>
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In 25 unrelated patients with Apert syndrome (<a href="/entry/101200">101200</a>), <a href="#112" class="mim-tip-reference" title="Wilkie, A. O. M., Slaney, S. F., Oldridge, M., Poole, M. D., Ashworth, G. J., Hockley, A. D., Hayward, R. D., David, D. J., Pulleyn, L. J., Rutland, P., Malcolm, S., Winter, R. M., Reardon, W. <strong>Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.</strong> Nature Genet. 9: 165-172, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719344</a>] [<a href="https://doi.org/10.1038/ng0295-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719344">Wilkie et al. (1995)</a> identified a heterozygous 934C-G transversion in the FGFR2 gene, resulting in a ser252-to-trp (S252W) substitution within a highly conserved linker region between the second and third extracellular immunoglobulin (Ig) domains of the protein. The mutation occurs within a CpG dinucleotide and is adjacent to another FGFR2 mutation causing Apert syndrome (P253R; <a href="#0011">176943.0011</a>), and was predicted to affect the orientation of the binding domains and thus alter the binding of growth factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7719344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 70 unrelated patients with Apert syndrome, <a href="#93" class="mim-tip-reference" title="Slaney, S. F., Oldridge, M., Hurst, J. A., Morriss-Kay, G. M., Hall, C. M., Poole, M. D., Wilkie, A. O. M. <strong>Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.</strong> Am. J. Hum. Genet. 58: 923-932, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651276</a>]" pmid="8651276">Slaney et al. (1996)</a> found that 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly of the hands and feet was more severe in those with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. <a href="#93" class="mim-tip-reference" title="Slaney, S. F., Oldridge, M., Hurst, J. A., Morriss-Kay, G. M., Hall, C. M., Poole, M. D., Wilkie, A. O. M. <strong>Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.</strong> Am. J. Hum. Genet. 58: 923-932, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651276</a>]" pmid="8651276">Slaney et al. (1996)</a> suggested that the opposite trends for severity of syndactyly and cleft palate in relation to the 2 mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, which are ligands for FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#72" class="mim-tip-reference" title="Passos-Bueno, M. R., Richieri-Costa, A., Sertie, A. L., Kneppers, A. <strong>Presence of the Apert canonical S252W FGFR2 mutation in a patient without severe syndactyly.</strong> J. Med. Genet. 35: 677-679, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9719378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9719378</a>] [<a href="https://doi.org/10.1136/jmg.35.8.677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9719378">Passos-Bueno et al. (1998)</a> reported a child whom they identified as having a Pfeiffer syndrome (<a href="/entry/101600">101600</a>)-like phenotype, without severe abnormalities of the upper and lower extremities, who had the S252W mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9719378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of crystal structure, <a href="#36" class="mim-tip-reference" title="Ibrahimi, O. A., Eliseenkova, A. V., Plotnikov, A. N., Yu, K., Ornitz, D. M., Mohammadi, M. <strong>Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.</strong> Proc. Nat. Acad. Sci. 98: 7182-7187, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11390973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11390973</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11390973[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121183798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11390973">Ibrahimi et al. (2001)</a> showed that both the S252W and P253R mutations associated with Apert syndrome introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity and resulting in a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11390973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Mantilla-Capacho, J. M., Arnaud, L., Diaz-Rodriguez, M., Barros-Nunez, P. <strong>Apert syndrome with preaxial polydactyly showing the typical mutation ser252trp in the FGFR2 gene.</strong> Genet. Counsel. 16: 403-406, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16440883/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16440883</a>]" pmid="16440883">Mantilla-Capacho et al. (2005)</a> reported a patient with Apert syndrome caused by the S252W mutation, which they stated resulted from a 755C-G transversion. The child did not have cleft palate, but did have preaxial polydactyly of the hands and feet. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16440883" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>From a cohort of 182 Spanish probands with craniosynostosis, <a href="#75" class="mim-tip-reference" title="Paumard-Hernandez, B., Berges-Soria, J., Barroso, E., Rivera-Pedroza, C. I., Perez-Carrizosa, V., Benito-Sanz, S., Lopez-Messa, E., Santos, F., Garcia-Recuero, I. I., Romance, A., Ballesta-Martinez, M. J., Lopez-Gonzalez, V., Campos-Barros, A., Cruz, J., Guillen-Navarro, E., Sanchez del Pozo, J., Lapunzina, P., Garcia-Minaur, S., Heath, K. E. <strong>Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.</strong> Europ. J. Hum. Genet. 23: 907-914, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25271085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25271085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25271085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25271085">Paumard-Hernandez et al. (2015)</a> identified 23 patients with Apert syndrome and mutations in FGFR2, 15 of whom had the S252W variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25271085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Endometrial Cancer, Somatic</em></strong></p><p>
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<a href="#79" class="mim-tip-reference" title="Pollock, P. M., Gartside, M. G., Dejeza, L. C., Powell, M. A., Mallon, M. A., Cancer Genome Project, Davies, H., Mohammadi, M., Futreal, P. A., Stratton, M. R., Trent, J. M., Goodfellow, P. J. <strong>Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes.</strong> Oncogene 26: 7158-7162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525745</a>] [<a href="https://doi.org/10.1038/sj.onc.1210529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525745">Pollock et al. (2007)</a> identified a somatic S252W mutation in 8 of 187 samples of endometrial carcinoma (<a href="/entry/608089">608089</a>), 7 of which were the endometrioid subtype and 1 of which was the serous subtype. It was the most common FGFR2 mutation identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs77543610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs77543610;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs77543610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs77543610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014193 OR RCV000489611 OR RCV000532721 OR RCV000762803 OR RCV001197223 OR RCV004532335" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014193, RCV000489611, RCV000532721, RCV000762803, RCV001197223, RCV004532335" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014193...</a>
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<p>In 15 unrelated patients with Apert syndrome (<a href="/entry/101200">101200</a>), <a href="#112" class="mim-tip-reference" title="Wilkie, A. O. M., Slaney, S. F., Oldridge, M., Poole, M. D., Ashworth, G. J., Hockley, A. D., Hayward, R. D., David, D. J., Pulleyn, L. J., Rutland, P., Malcolm, S., Winter, R. M., Reardon, W. <strong>Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.</strong> Nature Genet. 9: 165-172, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719344</a>] [<a href="https://doi.org/10.1038/ng0295-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719344">Wilkie et al. (1995)</a> identified a heterozygous 937C-G transversion in the FGFR2 gene, resulting in a pro253-to-arg (P253R) substitution within a highly conserved linker region between the second and third extracellular immunoglobulin (Ig) domains of the protein. The P253R mutation is adjacent to another FGFR2 mutation causing Apert syndrome (S252W; <a href="#0010">176943.0010</a>), and was predicted to affect the orientation of the binding domains and thus alter the binding of growth factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7719344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 70 unrelated patients with Apert syndrome, <a href="#93" class="mim-tip-reference" title="Slaney, S. F., Oldridge, M., Hurst, J. A., Morriss-Kay, G. M., Hall, C. M., Poole, M. D., Wilkie, A. O. M. <strong>Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.</strong> Am. J. Hum. Genet. 58: 923-932, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651276</a>]" pmid="8651276">Slaney et al. (1996)</a> found that 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly of the hands and feet was more severe in those with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. <a href="#93" class="mim-tip-reference" title="Slaney, S. F., Oldridge, M., Hurst, J. A., Morriss-Kay, G. M., Hall, C. M., Poole, M. D., Wilkie, A. O. M. <strong>Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.</strong> Am. J. Hum. Genet. 58: 923-932, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651276</a>]" pmid="8651276">Slaney et al. (1996)</a> suggested that the opposite trends for severity of syndactyly and cleft palate in relation to the 2 mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, which are ligands for FGFR2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8651276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of crystal structure, <a href="#36" class="mim-tip-reference" title="Ibrahimi, O. A., Eliseenkova, A. V., Plotnikov, A. N., Yu, K., Ornitz, D. M., Mohammadi, M. <strong>Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.</strong> Proc. Nat. Acad. Sci. 98: 7182-7187, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11390973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11390973</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11390973[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121183798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11390973">Ibrahimi et al. (2001)</a> showed that both the S252W and P253R mutations associated with Apert syndrome introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity and resulting in a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11390973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Andreou, A., Lamy, A., Layet, V., Cailliez, D., Gobet, F., Pfister, C., Menard, M., Frebourg, T. <strong>Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (pro253arg). (Letter)</strong> Am. J. Med. Genet. 140A: 2245-2247, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969861</a>] [<a href="https://doi.org/10.1002/ajmg.a.31430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16969861">Andreou et al. (2006)</a> reported a 4-year-old girl with Apert syndrome associated with a heterozygous P253R mutation. She also developed a low-grade papillary urothelial carcinoma of the bladder. No FGFR3 (<a href="/entry/134934">134934</a>) mutations were identified in the bladder tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>From a cohort of 182 Spanish probands with craniosynostosis, <a href="#75" class="mim-tip-reference" title="Paumard-Hernandez, B., Berges-Soria, J., Barroso, E., Rivera-Pedroza, C. I., Perez-Carrizosa, V., Benito-Sanz, S., Lopez-Messa, E., Santos, F., Garcia-Recuero, I. I., Romance, A., Ballesta-Martinez, M. J., Lopez-Gonzalez, V., Campos-Barros, A., Cruz, J., Guillen-Navarro, E., Sanchez del Pozo, J., Lapunzina, P., Garcia-Minaur, S., Heath, K. E. <strong>Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.</strong> Europ. J. Hum. Genet. 23: 907-914, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25271085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25271085</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25271085[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2014.205" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25271085">Paumard-Hernandez et al. (2015)</a> identified 23 patients Apert syndrome and mutations in FGFR2, 8 of whom had the S252W variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25271085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918495 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918495;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014194 OR RCV001037961 OR RCV001781263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014194, RCV001037961, RCV001781263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014194...</a>
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<p>In a sporadic case of Pfeiffer syndrome (<a href="/entry/101600">101600</a>), <a href="#88" class="mim-tip-reference" title="Rutland, P., Pulleyn, L. J., Reardon, W., Baraitser, M., Hayward, R., Jones, B., Malcolm, S., Winter, R. M., Oldridge, M., Slaney, S. F., Poole, M. D., Wilkie, A. O. M. <strong>Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes.</strong> Nature Genet. 9: 173-176, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719345</a>] [<a href="https://doi.org/10.1038/ng0295-173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719345">Rutland et al. (1995)</a> observed an A-to-C transversion at nucleotide 1033 changing thr to pro at position 341, adjacent to the cys342 residue that has been found altered in cases of Crouzon syndrome and Pfeiffer syndrome (e.g., <a href="#0001">176943.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7719345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014195 OR RCV000535651 OR RCV001588812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014195, RCV000535651, RCV001588812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014195...</a>
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<p>In a sporadic case of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#96" class="mim-tip-reference" title="Steinberger, D., Mulliken, J. B., Muller, U. <strong>Predisposition for cysteine substitutions in the immunoglobulin-like chain of FGFR2 in Crouzon syndrome.</strong> Hum. Genet. 96: 113-115, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607643</a>] [<a href="https://doi.org/10.1007/BF00214198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607643">Steinberger et al. (1995)</a> found a C-to-G transversion in nucleotide 1038, resulting in replacement of cysteine-343 by tryptophan. <a href="#51" class="mim-tip-reference" title="Ma, H. W., Lajeunie, E., Le Merrer, M., de Parseval, N., Serville, F., Weissenbach, J., Munnich, A., Renier, D. <strong>No evidence of genetic heterogeneity in Crouzon craniofacial dysostosis.</strong> Hum. Genet. 96: 731-735, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8522336/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8522336</a>] [<a href="https://doi.org/10.1007/BF00210308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8522336">Ma et al. (1995)</a> found the same mutation in a case of familial Crouzon syndrome. Studying 6 unrelated French families, they found in all of them evidence of close linkage to locus D10S1483 located on 10q25-q26. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7607643+8522336" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Hollway, G. E., Suthers, G. K., Haan, E. A., Thompson, E., David, D. J., Gecz, J., Mulley, J. C. <strong>Mutation detection in FGFR2 craniosynostosis syndromes.</strong> Hum. Genet. 99: 251-255, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9048930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9048930</a>] [<a href="https://doi.org/10.1007/s004390050348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9048930">Hollway et al. (1997)</a> found this mutation in a mother/daughter pair. The mother had features of mild Crouzon syndrome, while her daughter had features of Pfeiffer syndrome. Both had the identical 1205C-G nucleotide substitution (1205C-G numbering is based on <a href="#16" class="mim-tip-reference" title="Dionne, C. A., Crumley, G., Bellot, F., Kaplow, J. M., Searfoss, G., Ruta, M., Burgess, W. H., Jaye, M., Schlessinger, J. <strong>Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors.</strong> EMBO J. 9: 2685-2692, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1697263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1697263</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1990.tb07454.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1697263">Dionne et al. (1990)</a>; 1038C-G is based on the <a href="#34" class="mim-tip-reference" title="Houssaint, E., Blanquet, P. R., Champion-Arnaud, P., Gesnel, M. C., Torriglia, A., Courtois, Y., Breathnach, R. <strong>Related fibroblast growth factor receptor genes exist in the human genome.</strong> Proc. Nat. Acad. Sci. 87: 8180-8184, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2172978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2172978</a>] [<a href="https://doi.org/10.1073/pnas.87.20.8180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2172978">Houssaint et al. (1990)</a> sequence). The authors noted that other mutations in codon 342 are known to be accompanied by phenotypic variability: a G-to-A transition in codon 342 can result in either Crouzon syndrome or Pfeiffer syndrome (<a href="#0001">176943.0001</a>), while a T-to-C transition in codon 342 can lead to Crouzon syndrome, Pfeiffer syndrome, or Jackson-Weiss syndrome (<a href="#0002">176943.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2172978+1697263+9048930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918497 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918497;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918497" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014196 OR RCV000014197 OR RCV000415509 OR RCV001217538 OR RCV001572560" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014196, RCV000014197, RCV000415509, RCV001217538, RCV001572560" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014196...</a>
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<p>In affected members of a Crouzon syndrome (<a href="/entry/123500">123500</a>) kindred, <a href="#29" class="mim-tip-reference" title="Gorry, M. C., Preston, R. A., White, G. J., Zhang, Y., Singhal, V. K., Losken, H. W., Parker, M. G., Nwokoro, N. A., Post, J. C., Ehrlich, G. D. <strong>Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome.</strong> Hum. Molec. Genet. 4: 1387-1390, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581378</a>] [<a href="https://doi.org/10.1093/hmg/4.8.1387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581378">Gorry et al. (1995)</a> found a gln289-to-pro mutation due to an A-to-C transversion in nucleotide 878 in the 3-prime end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U), which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the gene. All previously reported Crouzon mutations had been found only in the FGFR2 spliceoform. <a href="#29" class="mim-tip-reference" title="Gorry, M. C., Preston, R. A., White, G. J., Zhang, Y., Singhal, V. K., Losken, H. W., Parker, M. G., Nwokoro, N. A., Post, J. C., Ehrlich, G. D. <strong>Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome.</strong> Hum. Molec. Genet. 4: 1387-1390, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7581378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7581378</a>] [<a href="https://doi.org/10.1093/hmg/4.8.1387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7581378">Gorry et al. (1995)</a> raised the question of possible second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes, which may determine specific aspects of the phenotypes of craniosynostosis syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7581378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Jackson-Weiss syndrome, <a href="#58" class="mim-tip-reference" title="Meyers, G. A., Day, D., Goldberg, R., Daentl, D. L., Przylepa, K. A., Abrams, L. J., Graham, J. M., Jr., Feingold, M., Moeschler, J. B., Rawnsley, E., Scott, A. F., Jabs, E. W. <strong>FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.</strong> Am. J. Hum. Genet. 58: 491-498, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644708</a>]" pmid="8644708">Meyers et al. (1996)</a> identified heterozygosity for a 1045A-C transversion in exon IIIa of the FGFR2 gene, resulting in a gln289-to-pro (Q289P) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Beare-Stevenson cutis gyrata syndrome (BSTVS; <a href="/entry/123790">123790</a>) is an autosomal dominant disorder characterized by furrowed skin (cutis gyrata), acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death. <a href="#82" class="mim-tip-reference" title="Przylepa, K. A., Paznekas, W., Zhang, M., Golabi, M., Bias, W., Bamshad, M. J., Carey, J. C., Hall, B. D., Stevenson, R., Orlow, S. J., Cohen, M. M., Jr., Jabs, E. W. <strong>Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.</strong> Nature Genet. 13: 492-494, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696350</a>] [<a href="https://doi.org/10.1038/ng0896-492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696350">Przylepa et al. (1996)</a> detected FGFR2 mutations in this disorder. In 3 sporadic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; 2 had the identical tyr375-to-cys mutation in the transmembrane domain and 1 had a ser372-to-cys mutation (<a href="#0016">176943.0016</a>) in the C-terminal end of the linker region between the immunoglobulin III-like and transmembrane domains. In 2 patients, neither of these mutations was found, suggesting to <a href="#82" class="mim-tip-reference" title="Przylepa, K. A., Paznekas, W., Zhang, M., Golabi, M., Bias, W., Bamshad, M. J., Carey, J. C., Hall, B. D., Stevenson, R., Orlow, S. J., Cohen, M. M., Jr., Jabs, E. W. <strong>Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.</strong> Nature Genet. 13: 492-494, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696350</a>] [<a href="https://doi.org/10.1038/ng0896-492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696350">Przylepa et al. (1996)</a> further genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#108" class="mim-tip-reference" title="Wang, T.-J., Huang, C.-B., Tsai, F.-J., Wu, J.-Y., Lai, R.-B., Hsiao, M. <strong>Mutation in the FGFR2 gene in a Taiwanese patient with Beare-Stevenson cutis gyrata syndrome.</strong> Clin. Genet. 61: 218-221, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12000365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12000365</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.610309.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12000365">Wang et al. (2002)</a> found the Y375C mutation in the FGFR2 gene in a Taiwanese patient with several clinical characteristics of Beare-Stevenson syndrome, including cutis gyrata, cloverleaf skull, prominent eyes, cleft palate, ear defects, and a protruding umbilical stump. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12000365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with Beare-Stevenson syndrome, <a href="#106" class="mim-tip-reference" title="Vargas, R. A. P., Maegawa, G. H. B., Taucher, S. C., Leite, J. C. L., Sanz, P., Cifuentes, J., Parra, M., Munoz, H., Maranduba, C. M., Passos-Bueno, M. R. <strong>Beare-Stevenson syndrome: two South American patients with FGFR2 analysis.</strong> Am. J. Med. Genet. 121A: 41-46, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12900900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12900900</a>] [<a href="https://doi.org/10.1002/ajmg.a.20101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12900900">Vargas et al. (2003)</a> identified the Y375C mutation. Both presented at birth with craniofacial anomalies, variable cutis gyrata in forehead and preauricular regions, prominent umbilical stump, and anteriorly placed anus. Both required mechanical ventilation for respiratory support and died before 50 days of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12900900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Pollock, P. M., Gartside, M. G., Dejeza, L. C., Powell, M. A., Mallon, M. A., Cancer Genome Project, Davies, H., Mohammadi, M., Futreal, P. A., Stratton, M. R., Trent, J. M., Goodfellow, P. J. <strong>Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes.</strong> Oncogene 26: 7158-7162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525745</a>] [<a href="https://doi.org/10.1038/sj.onc.1210529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525745">Pollock et al. (2007)</a> identified a somatic Y375C mutation in 2 unrelated samples of endometrial carcinoma (<a href="/entry/608089">608089</a>) of the endometrioid subtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525745" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121913477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913477;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121913477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121913477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>See <a href="#0015">176943.0015</a> and <a href="#82" class="mim-tip-reference" title="Przylepa, K. A., Paznekas, W., Zhang, M., Golabi, M., Bias, W., Bamshad, M. J., Carey, J. C., Hall, B. D., Stevenson, R., Orlow, S. J., Cohen, M. M., Jr., Jabs, E. W. <strong>Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.</strong> Nature Genet. 13: 492-494, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696350</a>] [<a href="https://doi.org/10.1038/ng0896-492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696350">Przylepa et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Fonseca, R., Costa-Lima, M. A., Cosentino, V., Orioli, I. M. <strong>Second case of Beare-Stevenson syndrome with an FGFR2 ser372cys mutation.</strong> Am. J. Med. Genet. 146A: 658-660, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18247426/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18247426</a>] [<a href="https://doi.org/10.1002/ajmg.a.32176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18247426">Fonseca et al. (2008)</a> reported a girl with Beare-Stevenson cutis gyrata syndrome (BSTVS; <a href="/entry/123790">123790</a>) who had a de novo heterozygous 1115C-G transversion in exon 11 of the FGFR2 gene, resulting in a ser372-to-cys (S372C) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18247426" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with Apert syndrome (<a href="/entry/101200">101200</a>), <a href="#67" class="mim-tip-reference" title="Oldridge, M., Lunt, P. W., Zackai, E. H., McDonald-McGinn, D. M., Muenke, M., Moloney, D. M., Twigg, S. R. F., Heath, J. K., Howard, T. D., Hoganson, G., Gagnon, D. M., Jabs, E. W., Wilkie, A. O. M. <strong>Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.</strong> Hum. Molec. Genet. 6: 137-143, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002682</a>] [<a href="https://doi.org/10.1093/hmg/6.1.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002682">Oldridge et al. (1997)</a> identified a CG-to-TT change in the FGFR2 gene, resulting in a ser252-to-phe (S252F) substitution. This was said to be the first noncanonical mutation to be identified in Apert syndrome, its rarity being explained by the requirement for 2 residues of the serine codon to be mutated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9002682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Lajeunie, E., Cameron, R., El Ghouzzi, V., de Parseval, N., Journeau, P., Gonzales, M., Delezoide, A.-L., Bonaventure, J., Le Merrer, M., Renier, D. <strong>Clinical variability in patients with Apert's syndrome.</strong> J. Neurosurg. 90: 443-447, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10067911</a>] [<a href="https://doi.org/10.3171/jns.1999.90.3.0443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10067911">Lajeunie et al. (1999)</a> identified the S252F substitution in a fetus with Apert syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10067911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#67" class="mim-tip-reference" title="Oldridge, M., Lunt, P. W., Zackai, E. H., McDonald-McGinn, D. M., Muenke, M., Moloney, D. M., Twigg, S. R. F., Heath, J. K., Howard, T. D., Hoganson, G., Gagnon, D. M., Jabs, E. W., Wilkie, A. O. M. <strong>Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.</strong> Hum. Molec. Genet. 6: 137-143, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002682</a>] [<a href="https://doi.org/10.1093/hmg/6.1.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002682">Oldridge et al. (1997)</a> identified a double amino acid substitution (ser252phe and pro253ser) resulting from a CGC-to-TCT mutation in the FGFR2 gene as the cause of a Pfeiffer syndrome (<a href="/entry/101600">101600</a>) variant. The clinical features in the isolated case were mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The description of independent, complex nucleotide substitutions involving identical nucleotides (see <a href="#0017">176943.0017</a>) was unprecedented. <a href="#67" class="mim-tip-reference" title="Oldridge, M., Lunt, P. W., Zackai, E. H., McDonald-McGinn, D. M., Muenke, M., Moloney, D. M., Twigg, S. R. F., Heath, J. K., Howard, T. D., Hoganson, G., Gagnon, D. M., Jabs, E. W., Wilkie, A. O. M. <strong>Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2.</strong> Hum. Molec. Genet. 6: 137-143, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9002682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9002682</a>] [<a href="https://doi.org/10.1093/hmg/6.1.137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9002682">Oldridge et al. (1997)</a> speculated that this may result from functional selection of FGFR mutations in sperm. In both of these complex mutations, the 934C-T substitution was present. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9002682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918499 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918499;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014203 OR RCV002254264 OR RCV003150929 OR RCV004532337" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014203, RCV002254264, RCV003150929, RCV004532337" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014203...</a>
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<p>In a patient with severe Pfeiffer phenotype (<a href="/entry/101600">101600</a>), <a href="#101" class="mim-tip-reference" title="Tartaglia, M., Valeri, S., Velardi, F., Di Rocco, C., Battaglia, P. A. <strong>Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome.</strong> Hum. Genet. 99: 602-606, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150725</a>] [<a href="https://doi.org/10.1007/s004390050413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150725">Tartaglia et al. (1997)</a> reported a de novo 870G-C transversion in exon IIIa of the FGFR2 gene, resulting in a trp290-to-cys (W290C) mutation. The patient had cloverleaf skull deformity as well as the other typical ocular, hand, and foot anomalies seen in Pfeiffer syndrome. Missense mutations at codon 290 of FGFR2 had been reported previously in Crouzon syndrome, but not in Pfeiffer syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 CROUZON SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918500 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918500;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014204 OR RCV002513037" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014204, RCV002513037" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014204...</a>
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<p>In 4 members of a 3-generation family with Crouzon syndrome (<a href="/entry/123500">123500</a>) and plagiocephaly, <a href="#95" class="mim-tip-reference" title="Steinberger, D., Collmann, H., Schmalenberger, B., Muller, U. <strong>A novel mutation (A886G) in exon 5 of FGFR2 in members of a family with Crouzon phenotype and plagiocephaly.</strong> J. Med. Genet. 34: 420-422, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9152842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9152842</a>] [<a href="https://doi.org/10.1136/jmg.34.5.420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9152842">Steinberger et al. (1997)</a> reported an A-to-G transition at nucleotide 886 in exon 5 of FGFR2, resulting in a lys292-to-glu substitution in Ig-like loop 3 of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9152842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0021 CROUZON SYNDROME</strong>
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FGFR2, TRP290ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918501;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014205 OR RCV000537718 OR RCV001549469" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014205, RCV000537718, RCV001549469" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014205...</a>
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<p>A trp290-to-arg substitution was observed by <a href="#68" class="mim-tip-reference" title="Oldridge, M., Wilkie, A. O. M., Slaney, S. F., Poole, M. D., Pulleyn, L. J., Rutland, P., Hockley, A. D., Wake, M. J. C., Goldin, J. H., Winter, R. M., Reardon, W., Malcolm, S. <strong>Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome.</strong> Hum. Molec. Genet. 4: 1077-1082, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7655462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7655462</a>] [<a href="https://doi.org/10.1093/hmg/4.6.1077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7655462">Oldridge et al. (1995)</a> in a patient with classic Crouzon syndrome (<a href="/entry/123500">123500</a>). The amino acid substitution in this case resulted from a change of codon 290 from TGG (trp) to CGG (arg). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7655462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 CROUZON SYNDROME</strong>
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FGFR2, TRP290GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918501 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918501;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014206 OR RCV004724741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014206, RCV004724741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014206...</a>
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<p>A trp290-to-gly substitution was observed in an atypically mild form of Crouzon syndrome (<a href="/entry/123500">123500</a>) by <a href="#71" class="mim-tip-reference" title="Park, W.-J., Meyers, G. A., Li, X., Theda, C., Day, D., Orlow, S. J., Jones, M. C., Jabs, E. W. <strong>Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.</strong> Hum. Molec. Genet. 4: 1229-1233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528214</a>] [<a href="https://doi.org/10.1093/hmg/4.7.1229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528214">Park et al. (1995)</a>. The amino acid substitution in this case resulted from a change of codon 290 from TGG (trp) to GGG (gly). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 SAETHRE-CHOTZEN SYNDROME</strong>
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FGFR2, VAL-VAL DEL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879253718 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879253718;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879253718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879253718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014207" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014207" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014207</a>
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<p>In a molecular study of 32 unrelated patients with features of Saethre-Chotzen syndrome (SCS; <a href="/entry/101400">101400</a>), a common autosomal dominant condition of craniosynostosis and limb anomalies, <a href="#76" class="mim-tip-reference" title="Paznekas, W. A., Cunningham, M. L., Howard, T. D., Korf, B. R., Lipson, M. H., Grix, A. W., Feingold, M., Goldberg, R., Borochowitz, Z., Aleck, K., Mulliken, J., Yin, M., Jabs, E. W. <strong>Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.</strong> Am. J. Hum. Genet. 62: 1370-1380, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585583</a>] [<a href="https://doi.org/10.1086/301855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585583">Paznekas et al. (1998)</a> found a single patient who had a val-val (codons 269 and 270) deletion in the FGFR2 gene. The patient had all the features, except digital anomalies, that occur in 33% or more of all patients with mutations in the TWIST1 gene (<a href="/entry/601622">601622</a>), which is the predominant site of mutations in this syndrome. The most common phenotypic features were coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability was present for either TWIST mutations or FGFR mutations. The overlapping clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition, such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes, supported the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans. <a href="#10" class="mim-tip-reference" title="Chun, K., Teebi, A. S., Jung, J. H., Kennedy, S., Laframboise, R., Meschino, W. S., Nakabayashi, K., Scherer, S. W., Roy, P. N., Teshima, I. <strong>Genetic analysis of patients with the Saethre-Chotzen phenotype.</strong> Am. J. Med. Genet. 110: 136-143, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12116251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12116251</a>] [<a href="https://doi.org/10.1002/ajmg.10400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12116251">Chun et al. (2002)</a> stated that the photograph shown of this patient was at variance with Saethre-Chotzen syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12116251+9585583" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0024 PFEIFFER SYNDROME, TYPE III</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918502 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918502;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014208 OR RCV000014209 OR RCV000256107 OR RCV000415503 OR RCV000528973 OR RCV003313920 OR RCV004737152" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014208, RCV000014209, RCV000256107, RCV000415503, RCV000528973, RCV003313920, RCV004737152" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014208...</a>
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<p><a href="#11" class="mim-tip-reference" title="Cohen, M. M., Jr. <strong>Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis.</strong> Am. J. Med. Genet. 45: 300-307, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8434615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8434615</a>] [<a href="https://doi.org/10.1002/ajmg.1320450305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8434615">Cohen (1993)</a> defined 3 clinical subtypes of Pfeiffer syndrome (<a href="/entry/101600">101600</a>). Type I is the common 'classic' type, presenting with craniosynostosis and broad thumbs and first toes in patients with normal or near-normal intelligence. Soft tissue syndactyly, symphalangism, and elbow ankylosis may be present. This condition is compatible with survival and reproduction; thus it frequently is familial, inherited as an autosomal dominant. Pfeiffer syndrome type II is more severe than type I, presenting with cloverleaf skull due to pansynostosis, severe ocular proptosis, and central nervous system involvement; a variety of low-frequency abnormalities, such as intestinal malrotation and tracheal stenosis also occur in this disorder. Elbow ankylosis occurs with the highest frequency in this type. Because of early death and failure to reproduce, this phenotype has been observed only as a sporadic mutation. Similarly severely affected cases, but without cloverleaf skull, have been called Pfeiffer syndrome type III. <a href="#30" class="mim-tip-reference" title="Gripp, K. W., Stolle, C. A., McDonald-McGinn, D. M., Markowitz, R. I., Bartlett, S. P., Katowitz, J. A., Muenke, M., Zackai, E. H. <strong>Phenotype of the fibroblast growth factor receptor 2 ser351-to-cys mutation: Pfeiffer syndrome type III.</strong> Am. J. Med. Genet. 78: 356-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714439</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980724)78:4<356::aid-ajmg10>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9714439">Gripp et al. (1998)</a> found a ser351-to-cys (S351C) mutation in the FGFR2 gene in a patient considered to have Pfeiffer syndrome type III. The patient had pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal nonrotation, and severe developmental delay. Skeletal abnormalities included bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The patient was unusual for the lack of broad thumbs. The patient most closely resembled one described by <a href="#44" class="mim-tip-reference" title="Kerr, N. C., Wilroy, R. S., Jr., Kaufman, R. A. <strong>Type 3 Pfeiffer syndrome with normal thumbs.</strong> Am. J. Med. Genet. 66: 138-143, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958319</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961211)66:2<138::AID-AJMG3>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8958319">Kerr et al. (1996)</a> as a case of Pfeiffer syndrome type III with normal thumbs. In a note added in proof, <a href="#30" class="mim-tip-reference" title="Gripp, K. W., Stolle, C. A., McDonald-McGinn, D. M., Markowitz, R. I., Bartlett, S. P., Katowitz, J. A., Muenke, M., Zackai, E. H. <strong>Phenotype of the fibroblast growth factor receptor 2 ser351-to-cys mutation: Pfeiffer syndrome type III.</strong> Am. J. Med. Genet. 78: 356-360, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714439</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980724)78:4<356::aid-ajmg10>3.0.co;2-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9714439">Gripp et al. (1998)</a> stated that heterozygosity for a cys342-to-arg substitution (<a href="#0002">176943.0002</a>) of the FGFR2 gene had been found in the patient reported by <a href="#44" class="mim-tip-reference" title="Kerr, N. C., Wilroy, R. S., Jr., Kaufman, R. A. <strong>Type 3 Pfeiffer syndrome with normal thumbs.</strong> Am. J. Med. Genet. 66: 138-143, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8958319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8958319</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961211)66:2<138::AID-AJMG3>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8958319">Kerr et al. (1996)</a>. Thus Pfeiffer syndrome appears to be heterogeneous. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8434615+9714439+8958319" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Okajima, K., Robinson, L. K., Hart, M. A., Abuelo, D. N., Cowan, L. S., Hasegawa, T., Maumenee, I. H., Jabs, E. W. <strong>Ocular anterior chamber dysgenesis in craniosynostosis syndromes with a fibroblast growth factor receptor 2 mutation.</strong> Am. J. Med. Genet. 85: 160-170, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10406670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10406670</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990716)85:2<160::aid-ajmg11>3.0.co;2-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10406670">Okajima et al. (1999)</a> evaluated 3 unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles. Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanel, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/atresia, midface hypoplasia, and elbow contractures were also present. These patients had airway compromise and seizures, and 2 died by age 15 months. All 3 cases were found to have the same FGFR2 S351C (1231C-to-G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding. Seven patients with isolated Peters anomaly, 2 patients with Peters plus syndrome, and 3 cases of typical Antley-Bixler syndrome were screened for this mutation, but none was found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10406670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with clinical manifestations that they found consistent with those of Antley-Bixler syndrome (ABS2; <a href="/entry/207410">207410</a>), <a href="#9" class="mim-tip-reference" title="Chun, K., Siegel-Bartelt, J., Chitayat, D., Phillips, J., Ray, P. N. <strong>FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.</strong> Am. J. Med. Genet. 77: 219-224, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605588</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980518)77:3<219::aid-ajmg6>3.0.co;2-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9605588">Chun et al. (1998)</a> identified a heterozygous C-to-G transversion at nucleotide 1064 of the FGFR2 gene, resulting in an S351C substitution in the IgIII domain of the protein. In addition to craniosynostosis and elbow ankylosis, the patient presented with severe spinal dysraphism. <a href="#28" class="mim-tip-reference" title="Gorlin, R. J. <strong>Patient described by Chun et al. may not present Antley-Bixler syndrome. (Letter)</strong> Am. J. Med. Genet. 83: 64 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10076886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10076886</a>]" pmid="10076886">Gorlin (1999)</a> and <a href="#31" class="mim-tip-reference" title="Gripp, K. W., Zackai, E. H., Cohen, M. M., Jr. <strong>Not Antley-Bixler syndrome. (Letter)</strong> Am. J. Med. Genet. 83: 65-66, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10076887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10076887</a>]" pmid="10076887">Gripp et al. (1999)</a> suggested that the patient of <a href="#9" class="mim-tip-reference" title="Chun, K., Siegel-Bartelt, J., Chitayat, D., Phillips, J., Ray, P. N. <strong>FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.</strong> Am. J. Med. Genet. 77: 219-224, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605588</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980518)77:3<219::aid-ajmg6>3.0.co;2-k" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9605588">Chun et al. (1998)</a> did not have Antley-Bixler syndrome but a nonspecific craniosynostosis syndrome. <a href="#8" class="mim-tip-reference" title="Chitayat, D., Chun, K. <strong>Reply to the letter to the editor by Gripp et al.--'not Antley-Bixler syndrome'. (Letter)</strong> Am. J. Med. Genet. 83: 67-68, 1999."None>Chitayat and Chun (1999)</a> in response reiterated the importance of looking for a mutation in the FGFR2 gene prior to informing parents that the recurrence risk of a similar condition is 25%. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10076886+9605588+10076887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 patients with Antley-Bixler syndrome, <a href="#83" class="mim-tip-reference" title="Reardon, W., Smith, A., Honour, J. W., Hindmarsh, P., Das, D., Rumsby, G., Nelson, I., Malcolm, S., Ades, L., Sillence, D., Kumar, D., DeLozier-Blanchet, C., McKee, S., Kelly, T., McKeehan, W. L., Baraitser, M., Winter, R. M. <strong>Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?</strong> J. Med. Genet. 37: 26-32, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10633130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10633130</a>] [<a href="https://doi.org/10.1136/jmg.37.1.26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10633130">Reardon et al. (2000)</a> identified the S351C substitution in the FGFR2 gene. The patients all had normal-appearing genitalia, and the steroid profile was normal in the 2 patients in whom it was carried out. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10633130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 fetuses diagnosed prenatally with severe Pfeiffer syndrome, <a href="#26" class="mim-tip-reference" title="Gonzales, M., Heuertz, S., Martinovic, J., Delahaye, S., Bazin, A., Loget, P., Pasquier, L., Le Merrer, M., Bonaventure, J. <strong>Vertebral anomalies and cartilaginous tracheal sleeve in three patients with Pfeiffer syndrome carrying the S351C FGFR2 mutation. (Letter)</strong> Clin. Genet. 68: 179-181, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15996217/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15996217</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00477.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15996217">Gonzales et al. (2005)</a> identified heterozygosity for the S351C substitution in the FGFR2 gene. All 3 patients had a cartilaginous tracheal sleeve at autopsy with no visible tracheal rings. In addition, all had vertebral anomalies, including cervical, thoracic, and lumbar fusion, and sacrococcygeal eversion was also present in 2 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15996217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 unrelated patients with Apert syndrome (<a href="/entry/101200">101200</a>), <a href="#69" class="mim-tip-reference" title="Oldridge, M., Zackai, E. H., McDonald-McGinn, D. M., Iseki, S., Morriss-Kay, G. M., Twigg, S. R. F., Johnson, D., Wall, S. A., Jiang, W., Theda, C., Jabs, E. W., Wilkie, A. O. M. <strong>De novo Alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.</strong> Am. J. Hum. Genet. 64: 446-461, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973282</a>] [<a href="https://doi.org/10.1086/302245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973282">Oldridge et al. (1999)</a> identified a 360-bp insertion of an Alu-element involving exon 9 of the FGFR2 gene. The insertion was just upstream of exon 9 in 1 case and within exon 9 in the other case. Both insertions had arisen de novo and both occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth factor receptor (KGFR) domain and bacterially-expressed kinase domain, respectively), which are differentially expressed in mouse limbs on embryonic day 13. <a href="#69" class="mim-tip-reference" title="Oldridge, M., Zackai, E. H., McDonald-McGinn, D. M., Iseki, S., Morriss-Kay, G. M., Twigg, S. R. F., Johnson, D., Wall, S. A., Jiang, W., Theda, C., Jabs, E. W., Wilkie, A. O. M. <strong>De novo Alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.</strong> Am. J. Hum. Genet. 64: 446-461, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973282</a>] [<a href="https://doi.org/10.1086/302245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973282">Oldridge et al. (1999)</a> examined splicing of exon 9 in RNA extracted from fibroblasts and keratinocytes from 1 Apert syndrome patient with an Alu insertion and 2 patients with Pfeiffer syndrome (<a href="/entry/101600">101600</a>) who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provided the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9973282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918503 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918503;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with Pfeiffer syndrome type 2 (<a href="/entry/101600">101600</a>), <a href="#81" class="mim-tip-reference" title="Priolo, M., Lerone, M., Baffico, M., Baldi, M., Ravazzolo, R., Cama, A., Capra, V., Silengo, M. <strong>Pfeiffer syndrome type 2 associated with a single amino acid deletion in the FGFR2 gene. (Letter)</strong> Clin. Genet. 58: 81-83, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945669/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945669</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2000.580116.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945669">Priolo et al. (2000)</a> found an in-frame deletion of 3 bp (GAC), which removed aspartic acid at position 273 of the FGFR2 protein. The patient, when seen at 1 month of age, had severe trigonocephaly with cloverleaf skull, flat occipitus, downward displacement of the ears to a horizontal position with respect to the neck, and severe ocular proptosis. Also present were radial clinodactyly of the thumbs and valgus deviation of the halluces. Imaging studies showed progressive triventricular hydrocephalus, callosal dysgenesis, and Chiari I malformation (<a href="/entry/118420">118420</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0028 CRANIOSYNOSTOSIS, NONSYNDROMIC UNICORONAL</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918504 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918504;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918504?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014212 OR RCV000856813 OR RCV001280733 OR RCV001851847 OR RCV002496355" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014212, RCV000856813, RCV001280733, RCV001851847, RCV002496355" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014212...</a>
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<p><a href="#41" class="mim-tip-reference" title="Johnson, D., Wall, S. A., Mann, S., Wilkie, A. O. M. <strong>A novel mutation, ala315 to ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?</strong> Europ. J. Hum. Genet. 8: 571-577, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10951518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10951518</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10951518">Johnson et al. (2000)</a> found a novel heterozygous mutation of the FGFR2 gene (943G-T, encoding the amino acid substitution ala315 to ser) in a girl with nonsyndromic unicoronal craniosynostosis. The mutation was also present in her mother and maternal grandfather who had mild facial asymmetry but did not have craniosynostosis. None of these individuals had the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history showed that the proband was in persistent breech presentation in utero and was delivered by cesarean section, at which time compression of the skull was apparent. <a href="#41" class="mim-tip-reference" title="Johnson, D., Wall, S. A., Mann, S., Wilkie, A. O. M. <strong>A novel mutation, ala315 to ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?</strong> Europ. J. Hum. Genet. 8: 571-577, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10951518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10951518</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10951518">Johnson et al. (2000)</a> proposed that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case fetal head constraint associated with breech position) was necessary for craniosynostosis to occur. To their knowledge, this was the first report of an interaction between the weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10951518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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GASTRIC CANCER, SOMATIC, INCLUDED
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FGFR2, SER267PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918505 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918505;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014213 OR RCV000408850 OR RCV000435703 OR RCV000690962 OR RCV002508123" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014213, RCV000408850, RCV000435703, RCV000690962, RCV002508123" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014213...</a>
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<p><a href="#12" class="mim-tip-reference" title="Cornejo-Roldan, L. R., Roessler, E., Muenke, M. <strong>Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome.</strong> Hum. Genet. 104: 425-431, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10394936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10394936</a>] [<a href="https://doi.org/10.1007/s004390050979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10394936">Cornejo-Roldan et al. (1999)</a> described a T-to-C transition at nucleotide 799 of the FGFR2 gene, resulting in a ser267-to-pro de novo mutation in each of 2 sporadic cases of Pfeiffer syndrome (<a href="/entry/101600">101600</a>). <a href="#40" class="mim-tip-reference" title="Jang, J.-H., Shin, K.-H., Park, J.-G. <strong>Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers.</strong> Cancer Res. 61: 3541-3543, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11325814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11325814</a>]" pmid="11325814">Jang et al. (2001)</a> found the same change as a somatic mutation in gastric cancer (<a href="/entry/137215">137215</a>). Thus, a heterozygous somatic mutation identical to a germinal activating mutation in FGFR2 in a craniosynostosis syndrome resulted in cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10394936+11325814" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879253719 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879253719;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879253719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879253719" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014215 OR RCV000694780" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014215, RCV000694780" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014215...</a>
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<p>In a patient with a mild phenotype typical of classic Pfeiffer syndrome (<a href="/entry/101600">101600</a>) of subtype 1, including brachycephaly with coronal synostosis and hypertelorism, <a href="#102" class="mim-tip-reference" title="Teebi, A. S., Kennedy, S., Chun, K., Ray, P. N. <strong>Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.</strong> Am. J. Med. Genet. 107: 43-47, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807866</a>] [<a href="https://doi.org/10.1002/ajmg.10125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807866">Teebi et al. (2002)</a> identified a 952G-A transition at the -1 position of 3-prime acceptor site of exon IIIc of the FGFR2 gene. They found a different mutation at the same site in a patient with a severe Pfeiffer syndrome phenotype; see <a href="#0031">176943.0031</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11807866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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FGFR2, 10-BP DEL/3-BP INS, NT952
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1589828632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1589828632;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1589828632" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1589828632" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014216" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014216" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014216</a>
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<p><a href="#102" class="mim-tip-reference" title="Teebi, A. S., Kennedy, S., Chun, K., Ray, P. N. <strong>Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.</strong> Am. J. Med. Genet. 107: 43-47, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807866</a>] [<a href="https://doi.org/10.1002/ajmg.10125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807866">Teebi et al. (2002)</a> described a complex deletion-insertion mutation at the 3-prime acceptor site of exon IIIc of the FGFR2 gene in a 17-year-old male with a severe Pfeiffer syndrome (<a href="/entry/101600">101600</a>) phenotype, within the spectrum of subtype 1, including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. They found a different mutation at the same site in a patient with a mild Pfeiffer syndrome phenotype; see <a href="#0030">176943.0030</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11807866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#114" class="mim-tip-reference" title="Wilkie, A. O. M. <strong>Abnormal spliceform expression associated with splice acceptor mutations in exon IIIc of FGFR2. (Letter)</strong> Am. J. Med. Genet. 111: 105 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12124745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12124745</a>] [<a href="https://doi.org/10.1002/ajmg.10486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12124745">Wilkie (2002)</a> pointed out that the expression of a distinct spliceoform of FGFR2 encoded by the alternatively spliced IIIb exon (termed FGFR2b or keratinocyte growth factor receptor) was demonstrated in fibroblasts from 5 patients with 3 different heterozygous mutations of this splice site (<a href="#69" class="mim-tip-reference" title="Oldridge, M., Zackai, E. H., McDonald-McGinn, D. M., Iseki, S., Morriss-Kay, G. M., Twigg, S. R. F., Johnson, D., Wall, S. A., Jiang, W., Theda, C., Jabs, E. W., Wilkie, A. O. M. <strong>De novo Alu-element insertions in FGFR2 identify a distinct pathological basis for Apert syndrome.</strong> Am. J. Hum. Genet. 64: 446-461, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9973282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9973282</a>] [<a href="https://doi.org/10.1086/302245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9973282">Oldridge et al., 1999</a>; <a href="#103" class="mim-tip-reference" title="Tsukuno, M., Suzuki, H., Eto, T. <strong>Pfeiffer syndrome caused by haploinsufficient mutation of FGFR2.</strong> J. Craniofac. Genet. Dev. Biol. 19: 183-188, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10731087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10731087</a>]" pmid="10731087">Tsukuno et al., 1999</a>). These patients had diagnoses of Pfeiffer syndrome (4 cases) and Apert syndrome (1 case). In accordance with the guidelines for nomenclature suggested by <a href="#14" class="mim-tip-reference" title="den Dunnen, J. T., Antonarakis, S. E. <strong>Nomenclature for the description of human sequence variations.</strong> Hum. Genet. 109: 121-124, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479744</a>] [<a href="https://doi.org/10.1007/s004390100505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479744">den Dunnen and Antonarakis (2001)</a>, <a href="#114" class="mim-tip-reference" title="Wilkie, A. O. M. <strong>Abnormal spliceform expression associated with splice acceptor mutations in exon IIIc of FGFR2. (Letter)</strong> Am. J. Med. Genet. 111: 105 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12124745/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12124745</a>] [<a href="https://doi.org/10.1002/ajmg.10486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12124745">Wilkie (2002)</a> clarified the designation for this mutation. The first nucleotide of exon IIIc is numbered 940. Based on this, the correct terminology for the indel mutation described by <a href="#102" class="mim-tip-reference" title="Teebi, A. S., Kennedy, S., Chun, K., Ray, P. N. <strong>Severe and mild phenotypes in Pfeiffer syndrome with splice acceptor mutations in exon IIIc of FGFR2.</strong> Am. J. Med. Genet. 107: 43-47, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11807866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11807866</a>] [<a href="https://doi.org/10.1002/ajmg.10125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11807866">Teebi et al. (2002)</a> should be c.940-3_946del10insACC. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11807866+9973282+11479744+12124745+10731087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918499 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918499;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014217 OR RCV000014218 OR RCV000655418 OR RCV001268882 OR RCV002490362" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014217, RCV000014218, RCV000655418, RCV001268882, RCV002490362" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014217...</a>
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<p>Whereas <a href="#101" class="mim-tip-reference" title="Tartaglia, M., Valeri, S., Velardi, F., Di Rocco, C., Battaglia, P. A. <strong>Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome.</strong> Hum. Genet. 99: 602-606, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150725</a>] [<a href="https://doi.org/10.1007/s004390050413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9150725">Tartaglia et al. (1997)</a> described a trp290-to-cys (W290C) substitution arising from a G-to-C transversion in the FGFR2 gene (<a href="#0019">176943.0019</a>) in a patient with severe Pfeiffer syndrome (<a href="/entry/101600">101600</a>), <a href="#89" class="mim-tip-reference" title="Schaefer, F., Anderson, C., Can, B., Say, B. <strong>Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case.</strong> Am. J. Med. Genet. 75: 252-255, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475591</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980123)75:3<252::aid-ajmg4>3.0.co;2-s" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9475591">Schaefer et al. (1998)</a> described a W290C mutation arising from a G-to-T transversion in a female infant diagnosed with Pfeiffer syndrome who had many overlapping features with Antley-Bixler syndrome (<a href="/entry/207410">207410</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9475591+9150725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Shotelersuk, V., Ittiwut, C., Srivuthana, S., Mahatumarat, C., Lerdlum, S., Wacharasindhu, S. <strong>Distinct craniofacial-skeletal-dermatological dysplasia in a patient with W290C mutation in FGFR2.</strong> Am. J. Med. Genet. 113: 4-8, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12400058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12400058</a>] [<a href="https://doi.org/10.1002/ajmg.10449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12400058">Shotelersuk et al. (2002)</a> described a 15-year-old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies at T9-T12 as well as ankyloses of humeral-radial-ulnar joints, intercarpal joints, distal interphalangeal joints of the fifth fingers, fibulo-tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was heterozygous for an 870G-T change resulting in a W290C substitution in the extracellular domain of the FGFR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12400058" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918506 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918506;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014219 OR RCV001851848 OR RCV003441716 OR RCV004532338" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014219, RCV001851848, RCV003441716, RCV004532338" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014219...</a>
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<p>In a patient with severe Pfeiffer syndrome (<a href="/entry/101600">101600</a>), <a href="#120" class="mim-tip-reference" title="Zankl, A., Jaeger, G., Bonafe, L., Boltshauser, E., Superti-Furga, A. <strong>Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome.</strong> Am. J. Med. Genet. 131A: 299-300, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523615</a>] [<a href="https://doi.org/10.1002/ajmg.a.30366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523615">Zankl et al. (2004)</a> identified a heterozygous 1694A-C transversion in the FGFR2 gene, resulting in a glu565-to-ala (E565A) substitution in the tyrosine kinase (TK) domain of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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SCAPHOCEPHALY, MAXILLARY RETRUSION, AND IMPAIRED INTELLECTUAL DEVELOPMENT, INCLUDED (1 family)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918507 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918507;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014220 OR RCV000014221 OR RCV003988821 OR RCV004760330 OR RCV005089251" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014220, RCV000014221, RCV003988821, RCV004760330, RCV005089251" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014220...</a>
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<p>In a father and 2 daughters, <a href="#13" class="mim-tip-reference" title="de Ravel, T. J. L., Taylor, I. B., Van Oostveldt, A. J. T., Fryns, J.-P., Wilkie, A. O. M. <strong>A further mutation of the FGFR2 tyrosine kinase domain in mild Crouzon syndrome.</strong> Europ. J. Hum. Genet. 13: 503-505, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15523492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15523492</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15523492">de Ravel et al. (2005)</a> identified a heterozygous 1576A-G transition in the FGFR2 gene, resulting in a lys526-to-glu (K526E) substitution in the tyrosine kinase I domain of the protein. The father and 1 of the daughters were diagnosed with Crouzon syndrome (<a href="/entry/123500">123500</a>), whereas the other daughter had neither facial dysmorphism nor hand or foot anomalies, indicating clinical nonpenetrance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15523492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In all 11 affected members of a 3-generation family with scaphocephaly, maxillary retrusion, and impaired intellectual development (<a href="/entry/609579">609579</a>), <a href="#55" class="mim-tip-reference" title="McGillivray, G., Savarirayan, R., Cox, T. C., Stojkoski, C., McNeil, R., Bankier, A., Bateman, J. F., Roscioli, T., Gardner, R. J. M., Lamande, S. R. <strong>Familial scaphocephaly syndrome caused by a novel mutation in the FGFR2 tyrosine kinase domain.</strong> J. Med. Genet. 42: 656-662, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061565/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061565</a>] [<a href="https://doi.org/10.1136/jmg.2004.027888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061565">McGillivray et al. (2005)</a> identified heterozygosity for the 1576A-G transition in exon 14 of the FGFR2 gene, resulting in the K526E substitution. The mutation was not found in 19 unaffected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061565" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918508 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918508;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014222 OR RCV001291623 OR RCV002513038 OR RCV004767007" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014222, RCV001291623, RCV002513038, RCV004767007" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014222...</a>
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<p>In a Dutch family and an English family, <a href="#87" class="mim-tip-reference" title="Rohmann, E., Brunner, H. G., Kayserili, H., Uyguner, O., Nurnberg, G., Lew, E. D., Dobbie, A., Eswarakumar, V. P., Uzumcu, A., Ulubil-Emeroglu, M., Leroy, J. G., Li, Y., and 9 others. <strong>Mutations in different components of FGF signaling in LADD syndrome.</strong> Nature Genet. 38: 414-417, 2006. Note: Erratum: Nature Genet. 38: 495 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501574</a>] [<a href="https://doi.org/10.1038/ng1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501574">Rohmann et al. (2006)</a> found that LADD syndrome (LADD1; <a href="/entry/149730">149730</a>) was associated with heterozygosity for a 1942G-A transition in exon 16 of the FGFR2 gene, predicting the substitution of a highly conserved ala648 by threonine (A648T). <a href="#87" class="mim-tip-reference" title="Rohmann, E., Brunner, H. G., Kayserili, H., Uyguner, O., Nurnberg, G., Lew, E. D., Dobbie, A., Eswarakumar, V. P., Uzumcu, A., Ulubil-Emeroglu, M., Leroy, J. G., Li, Y., and 9 others. <strong>Mutations in different components of FGF signaling in LADD syndrome.</strong> Nature Genet. 38: 414-417, 2006. Note: Erratum: Nature Genet. 38: 495 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501574</a>] [<a href="https://doi.org/10.1038/ng1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501574">Rohmann et al. (2006)</a> showed that the mutation probably originated independently in the 2 families, as it was not located on a common founder haplotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16501574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879253720 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879253720;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879253720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879253720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014223</a>
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<p>In a Turkish family with LADD syndrome (LADD1; <a href="/entry/149730">149730</a>), <a href="#87" class="mim-tip-reference" title="Rohmann, E., Brunner, H. G., Kayserili, H., Uyguner, O., Nurnberg, G., Lew, E. D., Dobbie, A., Eswarakumar, V. P., Uzumcu, A., Ulubil-Emeroglu, M., Leroy, J. G., Li, Y., and 9 others. <strong>Mutations in different components of FGF signaling in LADD syndrome.</strong> Nature Genet. 38: 414-417, 2006. Note: Erratum: Nature Genet. 38: 495 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501574</a>] [<a href="https://doi.org/10.1038/ng1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501574">Rohmann et al. (2006)</a> found a heterozygous 3-bp deletion in exon 16 of the FGFR2 gene, delta1947-AGA-1949, that led to substitution of the highly conserved arginine at position 649 by serine and to the deletion of the neighboring aspartic acid (R649S delta-asp650). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16501574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918509 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918509;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014224 OR RCV000414415" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014224, RCV000414415" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014224...</a>
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<p>In a case of LADD (LADD1; <a href="/entry/149730">149730</a>) from Belgium, <a href="#87" class="mim-tip-reference" title="Rohmann, E., Brunner, H. G., Kayserili, H., Uyguner, O., Nurnberg, G., Lew, E. D., Dobbie, A., Eswarakumar, V. P., Uzumcu, A., Ulubil-Emeroglu, M., Leroy, J. G., Li, Y., and 9 others. <strong>Mutations in different components of FGF signaling in LADD syndrome.</strong> Nature Genet. 38: 414-417, 2006. Note: Erratum: Nature Genet. 38: 495 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16501574/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16501574</a>] [<a href="https://doi.org/10.1038/ng1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16501574">Rohmann et al. (2006)</a> identified a de novo FGFR2 mutation, 1882G-A, that resulted in substitution of ala628 by thr (A628T). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16501574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Lew, E. D., Bae, J. H., Rohmann, E., Wollnik, B., Schlessinger, J. <strong>Structural basis for reduced FGFR2 activity in LADD syndrome: implications for FGFR autoinhibition and activation.</strong> Proc. Nat. Acad. Sci. 104: 19802-19807, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18056630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18056630</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18056630[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0709905104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18056630">Lew et al. (2007)</a> presented the crystal structure of FGFR2 with the A628T mutation in complex with a nucleotide analog. The mutation altered the configuration of key residues in the catalytic pocket that are essential for substrate coordination, resulting in reduced tyrosine kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18056630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879253721 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879253721;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879253721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879253721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014225 OR RCV000014226 OR RCV001254178 OR RCV001382547 OR RCV002273930" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014225, RCV000014226, RCV001254178, RCV001382547, RCV002273930" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014225...</a>
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<p>In a patient with Pfeiffer syndrome (<a href="/entry/101600">101600</a>), <a href="#12" class="mim-tip-reference" title="Cornejo-Roldan, L. R., Roessler, E., Muenke, M. <strong>Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome.</strong> Hum. Genet. 104: 425-431, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10394936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10394936</a>] [<a href="https://doi.org/10.1007/s004390050979" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10394936">Cornejo-Roldan et al. (1999)</a> identified a de novo 1084A-G transition at the +3 position (1084+3A-G) of the 5-prime donor site of exon IIIc of the FGFR2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10394936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with mild features of Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#42" class="mim-tip-reference" title="Kan, R., Twigg, S. R. F., Berg, J., Wang, L., Jin, F., Wilkie, A. O. M. <strong>Expression analysis of an FGFR2 IIIc 5-prime splice site mutation (1084+3A-G).</strong> J. Med. Genet. 41: e108, 2004. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15286168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15286168</a>] [<a href="https://doi.org/10.1136/jmg.2004.018507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15286168">Kan et al. (2004)</a> identified heterozygosity for the 1084+3A-G splice site transition in the FGFR2 gene. Although both A and G are consensus nucleotides at the +3 position of the 5-prime splice site, the authors calculated that the A-G substitution reduces the strength of the splice site and, using DNA sequencing and hybridization to specific oligonucleotides, demonstrated that the mutation causes a switch to the use of a known cryptic 5-prime splice site (see <a href="#0006">176943.0006</a>) within the upstream exon IIIc. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15286168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918510 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918510;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918510" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014227 OR RCV002513039" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014227, RCV002513039" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014227...</a>
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<p>In a patient with Pfeiffer syndrome (<a href="/entry/101600">101600</a>) who had Apert syndrome (<a href="/entry/101200">101200</a>)-like syndactyly, <a href="#65" class="mim-tip-reference" title="Nagase, T., Nagase, M., Hirose, S., Ohmori, K. <strong>Mutations in fibroblast growth factor receptor 2 gene and craniosynostotic syndromes in Japanese children.</strong> J. Craniofac. Surg. 9: 162-170, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9586546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9586546</a>] [<a href="https://doi.org/10.1097/00001665-199803000-00015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9586546">Nagase et al. (1998)</a> detected heterozygosity for an asp321-to-ala (D321A) amino acid substitution in FGFR2. The mutation occurs in the alternatively spliced beta-C-prime-beta-E loop of FGFR2c. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9586546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Heterozygosity for the D321A mutation had been described by <a href="#48" class="mim-tip-reference" title="Lajeunie, E., Ma, H. W., Bonaventure, J., Munnich, A., Le Merrer, M., Renier, D. <strong>FGFR2 mutations in Pfeiffer syndrome. (Letter)</strong> Nature Genet. 9: 108 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7719333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7719333</a>] [<a href="https://doi.org/10.1038/ng0295-108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7719333">Lajeunie et al. (1995)</a> in a patient with Pfeiffer syndrome. The substitution resulted from a 974A-C transversion in the FGFR2 gene and was not found in 80 normal controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7719333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Ibrahimi, O. A., Zhang, F., Eliseenkova, A. V., Itoh, N., Linhardt, R. J., Mohammadi, M. <strong>Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities.</strong> Hum. Molec. Genet. 13: 2313-2324, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15282208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15282208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15282208[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddh235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15282208">Ibrahimi et al. (2004)</a> demonstrated that the D321A mutation increased the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. Additionally, it violated FGFR2c ligand binding specificity and enabled this receptor to bind FGF10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15282208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0040 BEARE-STEVENSON CUTIS GYRATA SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554930637 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554930637;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1554930637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1554930637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022731" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022731" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022731</a>
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<p>In a boy with Beare-Stevenson cutis gyrata syndrome (BSTVS; <a href="/entry/123790">123790</a>), <a href="#94" class="mim-tip-reference" title="Slavotinek, A., Crawford, H., Golabi, M., Tao, C., Perry, H., Oberoi, S., Vargervik, K., Friez, M. <strong>Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome. (Letter)</strong> Am. J. Med. Genet. 149A: 1814-1817, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19610084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19610084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19610084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.32947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19610084">Slavotinek et al. (2009)</a> identified a de novo heterozygous 63-bp deletion starting in exon 8 of the FGFR2 gene (1506del63), predicting the loss of 21 amino acids from the IgIIIa domain. <a href="#94" class="mim-tip-reference" title="Slavotinek, A., Crawford, H., Golabi, M., Tao, C., Perry, H., Oberoi, S., Vargervik, K., Friez, M. <strong>Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome. (Letter)</strong> Am. J. Med. Genet. 149A: 1814-1817, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19610084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19610084</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19610084[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.32947" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19610084">Slavotinek et al. (2009)</a> suggested that the deletion may alter the splicing of isoform IIIc, resulting in illegitimate expression and thus a gain of function of FGFR2b. Striking craniofacial features were present at birth, including cloverleaf skull with fused sutures, ocular proptosis with hypoplasia of the supraorbital ridges, hypertelorism, strabismus, deep creases below the eyes, a high nasal bridge, midface hypoplasia, high-arched and narrow palate, and bilateral ear creases. Cutaneous features included cutis gyrata and acanthosis nigricans of the posterior scalp, small skin tags, excess neck skin, and a prominent umbilicus with redundant skin. Hydrocephalus with Arnold-Chiari malformation was present, but neurodevelopment was normal. Unusual features included multiple neonatal teeth, gingival hyperplasia, and atresia of the external ear canals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19610084" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906676;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022732 OR RCV002513173" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022732, RCV002513173" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022732...</a>
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<p>In a Brazilian patient with Crouzon syndrome (<a href="/entry/123500">123500</a>), <a href="#73" class="mim-tip-reference" title="Passos-Bueno, M. R., Sertie, A. L., Richieri-Costa, A., Alonso, L. G., Zatz, M., Alonso, N., Brunoni, D., Ribeiro, S. F. M. <strong>Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses.</strong> Am. J. Med. Genet. 78: 237-241, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9677057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9677057</a>]" pmid="9677057">Passos-Bueno et al. (1998)</a> identified a heterozygous 1188G-C transversion in exon IIIc of the FGFR2 gene, resulting in an ala337-to-pro (A337P) substitution in a conserved residue. The mutation was not found in 40 control chromosomes. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9677057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906676;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022733" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022733" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022733</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to a craniosynostosis phenotype has not been confirmed.</p><p><a href="#110" class="mim-tip-reference" title="Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., Taylor, I. B., Rannan-Eliya, S. V., Byren, J. C., Wall, S. A., Ramos, L., Venancio, M., Hurst, J. A., O'Rourke, A. W., Williams, L. J., Seller, A., Lester, T. <strong>Clinical dividends from the molecular genetic diagnosis of craniosynostosis.</strong> Am. J. Med. Genet. 143A: 1941-1949, 2007. Note: Republication with correction of an article originally published in Am. J. Med. Genet. 140A: 2631-2639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17621648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17621648</a>] [<a href="https://doi.org/10.1002/ajmg.a.31905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17621648">Wilkie et al. (2007)</a> identified a heterozygous 1009G-A transition in the FGFR2 gene, resulting in an ala337-to-thr (A337T) substitution, in a child with left unicoronal synostosis. She did not have Crouzonoid or other syndromic features. However, the same mutation was found in 6 additional family members without craniosynostosis, although 1 had midface hypoplasia and crowded teeth. <a href="#110" class="mim-tip-reference" title="Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., Taylor, I. B., Rannan-Eliya, S. V., Byren, J. C., Wall, S. A., Ramos, L., Venancio, M., Hurst, J. A., O'Rourke, A. W., Williams, L. J., Seller, A., Lester, T. <strong>Clinical dividends from the molecular genetic diagnosis of craniosynostosis.</strong> Am. J. Med. Genet. 143A: 1941-1949, 2007. Note: Republication with correction of an article originally published in Am. J. Med. Genet. 140A: 2631-2639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17621648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17621648</a>] [<a href="https://doi.org/10.1002/ajmg.a.31905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17621648">Wilkie et al. (2007)</a> noted that a mutation affecting the same codon (A337P; <a href="#0041">176943.0041</a>) had been identified in a patient with Crouzon syndrome (<a href="/entry/123500">123500</a>), suggesting that the A337T variant may be causally related to the phenotype in the proband with unicoronal synostosis. However, no functional studies were performed on the A337T variant. <a href="#110" class="mim-tip-reference" title="Wilkie, A. O. M., Bochukova, E. G., Hansen, R. M. S., Taylor, I. B., Rannan-Eliya, S. V., Byren, J. C., Wall, S. A., Ramos, L., Venancio, M., Hurst, J. A., O'Rourke, A. W., Williams, L. J., Seller, A., Lester, T. <strong>Clinical dividends from the molecular genetic diagnosis of craniosynostosis.</strong> Am. J. Med. Genet. 143A: 1941-1949, 2007. Note: Republication with correction of an article originally published in Am. J. Med. Genet. 140A: 2631-2639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17621648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17621648</a>] [<a href="https://doi.org/10.1002/ajmg.a.31905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17621648">Wilkie et al. (2007)</a> concluded that A337T showed either reduced penetrance or was of uncertain pathogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17621648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0043 BENT BONE DYSPLASIA SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906677 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906677;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022734 OR RCV000493423" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022734, RCV000493423" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022734...</a>
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<p>In 1 male and 2 female fetuses with a perinatal lethal bent bone dysplasia syndrome-1 (BBDS1; <a href="/entry/614592">614592</a>), <a href="#56" class="mim-tip-reference" title="Merrill, A. E., Sarukhanov, A., Krejci, P., Idoni, B., Camacho, N., Estrada, K. D., Lyons, K. M., Deixler, H., Robinson, H., Chitayat, D., Curry, C. J., Lachman, R. S., Wilcox, W. R., Krakow, D. <strong>Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.</strong> Am. J. Hum. Genet. 90: 550-557, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22387015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22387015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22387015">Merrill et al. (2012)</a> identified heterozygosity for a de novo 1172T-G transversion in exon 9 of the FGFR2 gene, resulting in a met391-to-arg (M391R) substitution that replaces a highly conserved hydrophobic residue with a positively charged polar amino acid in the transmembrane domain. The mutation was not present in parental DNA available from 2 of the cases, and was not found in 210 ethnically matched control alleles. Using diseased chondrocytes and a cell-based assay, <a href="#56" class="mim-tip-reference" title="Merrill, A. E., Sarukhanov, A., Krejci, P., Idoni, B., Camacho, N., Estrada, K. D., Lyons, K. M., Deixler, H., Robinson, H., Chitayat, D., Curry, C. J., Lachman, R. S., Wilcox, W. R., Krakow, D. <strong>Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.</strong> Am. J. Hum. Genet. 90: 550-557, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22387015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22387015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22387015">Merrill et al. (2012)</a> demonstrated that the M391R mutation selectively reduces plasma-membrane levels of FGFR2 and markedly diminishes the receptor's responsiveness to extracellular FGF (<a href="/entry/136350">136350</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22387015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0044" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0044 BENT BONE DYSPLASIA SYNDROME 1</strong>
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FGFR2, TYR381ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906678 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906678;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022735 OR RCV000190765 OR RCV000725446 OR RCV004528130" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022735, RCV000190765, RCV000725446, RCV004528130" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022735...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a female fetus with a perinatal lethal bent bone dysplasia syndrome-1 (BBDS1; <a href="/entry/614592">614592</a>), <a href="#56" class="mim-tip-reference" title="Merrill, A. E., Sarukhanov, A., Krejci, P., Idoni, B., Camacho, N., Estrada, K. D., Lyons, K. M., Deixler, H., Robinson, H., Chitayat, D., Curry, C. J., Lachman, R. S., Wilcox, W. R., Krakow, D. <strong>Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling.</strong> Am. J. Hum. Genet. 90: 550-557, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22387015/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22387015</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22387015[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.02.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22387015">Merrill et al. (2012)</a> identified heterozygosity for a 1141T-G transversion in exon 9 of the FGFR2 gene, resulting in a tyr381-to-asp (Y381D) substitution that replaces a highly conserved hydrophobic residue with a negatively charged polar amino acid in the transmembrane domain. Parental DNA was unavailable, but the mutation was not found in 210 ethnically matched control alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22387015" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Anderson1998" class="mim-anchor"></a>
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Anderson, J., Burns, H. D., Enriquez-Harris, P., Wilkie, A. O. M., Heath, J. K.
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<strong>Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand.</strong>
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Hum. Molec. Genet. 7: 1475-1483, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700203</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/7.9.1475" target="_blank">Full Text</a>]
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<a id="Andreou2006" class="mim-anchor"></a>
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Andreou, A., Lamy, A., Layet, V., Cailliez, D., Gobet, F., Pfister, C., Menard, M., Frebourg, T.
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<strong>Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (pro253arg). (Letter)</strong>
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Am. J. Med. Genet. 140A: 2245-2247, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16969861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16969861</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16969861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31430" target="_blank">Full Text</a>]
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<a id="Antoniou2008" class="mim-anchor"></a>
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Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., and 80 others.
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<strong>Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.</strong>
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Am. J. Hum. Genet. 82: 937-948, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18355772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18355772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18355772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18355772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.02.008" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Arman1998" class="mim-anchor"></a>
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<div class="">
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Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K., Lonai, P.
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<strong>Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development.</strong>
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Proc. Nat. Acad. Sci. 95: 5082-5087, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9560232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9560232</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9560232[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9560232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.95.9.5082" target="_blank">Full Text</a>]
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<a id="Arman1999" class="mim-anchor"></a>
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Arman, E., Haffner-Krausz, R., Gorivodsky, M., Lonai, P.
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<strong>Fgfr2 is required for limb outgrowth and lung-branching morphogenesis.</strong>
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Proc. Nat. Acad. Sci. 96: 11895-11899, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518547</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10518547[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.96.21.11895" target="_blank">Full Text</a>]
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<a id="Avraham1994" class="mim-anchor"></a>
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Avraham, K. B., Givol, D., Avivi, A., Yayon, A., Copeland, N. G., Jenkins, N. A.
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<strong>Mapping of murine fibroblast growth factor receptors refines regions of homology between mouse and human chromosomes.</strong>
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Genomics 21: 656-658, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959747</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7959747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1994.1330" target="_blank">Full Text</a>]
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<a id="Bagheri-Fam2015" class="mim-anchor"></a>
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Bagheri-Fam, S., Ono, M., Li, L., Zhao, L., Ryan, J., Lai, R., Katsura, Y., Rossello, F. J., Koopman, P., Scherer, G., Bartsch, O., Eswarakumar, J. V. P., Harley, V. R.
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<strong>FGFR2 mutation in 46,XY sex reversal with craniosynostosis.</strong>
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Hum. Molec. Genet. 24: 6699-6710, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26362256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26362256</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26362256[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26362256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv374" target="_blank">Full Text</a>]
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<a id="Chitayat1999" class="mim-anchor"></a>
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Chitayat, D., Chun, K.
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<strong>Reply to the letter to the editor by Gripp et al.--'not Antley-Bixler syndrome'. (Letter)</strong>
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Am. J. Med. Genet. 83: 67-68, 1999.
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Chun, K., Siegel-Bartelt, J., Chitayat, D., Phillips, J., Ray, P. N.
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<strong>FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.</strong>
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Am. J. Med. Genet. 77: 219-224, 1998.
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19980724)78:4<356::aid-ajmg10>3.0.co;2-h" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19980123)75:3<252::aid-ajmg4>3.0.co;2-s" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0436500100" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.97.26.14536" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30366" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 01/25/2022
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Marla J. F. O'Neill - updated : 3/18/2016<br>Ada Hamosh - updated : 4/11/2014<br>Marla J. F. O'Neill - updated : 4/24/2012<br>Cassandra L. Kniffin - updated : 1/4/2012<br>George E. Tiller - updated : 12/2/2011<br>Cassandra L. Kniffin - updated : 7/18/2011<br>George E. Tiller - updated : 3/31/2010<br>George E. Tiller - updated : 10/15/2009<br>Marla J. F. O'Neill - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 4/28/2008<br>Cassandra L. Kniffin - updated : 4/7/2008<br>Patricia A. Hartz - updated : 2/27/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 10/29/2007<br>Patricia A. Hartz - updated : 9/25/2007<br>Cassandra L. Kniffin - updated : 7/17/2007<br>Marla J. F. O'Neill - updated : 4/30/2007<br>Marla J. F. O'Neill - updated : 4/17/2007<br>George E. Tiller - updated : 4/5/2007<br>Marla J. F. O'Neill - updated : 3/13/2007<br>Cassandra L. Kniffin - updated : 12/18/2006<br>Cassandra L. Kniffin - updated : 7/11/2006<br>Marla J. F. O'Neill - updated : 5/24/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Marla J. F. O'Neill - updated : 4/6/2006<br>Cassandra L. Kniffin - updated : 2/8/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Victor A. McKusick - updated : 11/17/2005<br>Marla J. F. O'Neill - updated : 10/25/2005<br>Marla J. F. O'Neill - updated : 9/13/2005<br>Marla J. F. O'Neill - updated : 9/1/2005<br>Victor A. McKusick - updated : 4/26/2005<br>Victor A. McKusick - updated : 1/3/2005<br>Marla J. F. O'Neill - updated : 7/9/2004<br>Patricia A. Hartz - updated : 4/21/2004<br>Victor A. McKusick - updated : 2/13/2004<br>Victor A. McKusick - updated : 10/7/2003<br>Victor A. McKusick - updated : 8/25/2003<br>Ada Hamosh - updated : 8/12/2003<br>Victor A. McKusick - updated : 4/28/2003<br>Ada Hamosh - updated : 4/22/2003<br>Victor A. McKusick - updated : 11/7/2002<br>Victor A. McKusick - updated : 8/14/2002<br>Victor A. McKusick - updated : 8/8/2002<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 1/17/2002<br>Victor A. McKusick - updated : 9/19/2001<br>Victor A. McKusick - updated : 9/12/2001<br>Victor A. McKusick - updated : 8/1/2001<br>Victor A. McKusick - updated : 6/26/2001<br>Victor A. McKusick - updated : 4/17/2001<br>Victor A. McKusick - updated : 1/12/2001<br>Victor A. McKusick - updated : 11/2/2000<br>Ada Hamosh - updated : 10/25/2000<br>Victor A. McKusick - updated : 9/1/2000<br>Stylianos E. Antonarakis - updated : 6/7/2000<br>Victor A. McKusick - updated : 4/10/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Ada Hamosh - updated : 9/21/1999<br>Victor A. McKusick - updated : 7/20/1999<br>Victor A. McKusick - updated : 4/26/1999<br>Ada Hamosh - updated : 4/19/1999<br>Victor A. McKusick - updated : 2/5/1999<br>Michael J. Wright - updated : 11/16/1998<br>Victor A. McKusick - updated : 10/8/1998<br>Victor A. McKusick - updated : 9/17/1998<br>Victor A. McKusick - updated : 9/1/1998<br>Victor A. McKusick - updated : 7/1/1998<br>Clair A. Francomano - updated : 6/26/1998<br>Victor A. McKusick - updated : 6/11/1998<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 3/25/1998<br>Michael J. Wright - updated : 11/20/1997<br>Victor A. McKusick - updated : 10/14/1997<br>Ada Hamosh - updated : 7/10/1997<br>Victor A. McKusick - updated : 2/28/1997<br>Victor A. McKusick - updated : 2/17/1997<br>Moyra Smith - updated : 1/31/1997<br>Moyra Smith - updated : 1/31/1997<br>Moyra Smith - updated : 4/26/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 11/19/1990
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/07/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/04/2022<br>carol : 11/02/2022<br>carol : 11/01/2022<br>carol : 10/13/2022<br>carol : 01/25/2022<br>carol : 09/17/2018<br>alopez : 08/13/2018<br>carol : 08/10/2018<br>alopez : 08/09/2018<br>carol : 09/06/2016<br>joanna : 07/18/2016<br>alopez : 3/18/2016<br>alopez : 4/10/2015<br>alopez : 4/11/2014<br>terry : 4/1/2013<br>terry : 10/10/2012<br>carol : 9/19/2012<br>carol : 6/5/2012<br>carol : 5/1/2012<br>carol : 4/25/2012<br>terry : 4/24/2012<br>alopez : 4/12/2012<br>carol : 2/2/2012<br>ckniffin : 1/4/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>wwang : 7/22/2011<br>ckniffin : 7/18/2011<br>terry : 11/16/2010<br>alopez : 9/24/2010<br>terry : 5/28/2010<br>wwang : 4/14/2010<br>terry : 3/31/2010<br>carol : 3/16/2010<br>carol : 3/16/2010<br>carol : 3/15/2010<br>wwang : 10/16/2009<br>terry : 10/15/2009<br>wwang : 9/4/2009<br>terry : 8/27/2009<br>wwang : 9/9/2008<br>wwang : 5/1/2008<br>ckniffin : 4/28/2008<br>wwang : 4/9/2008<br>ckniffin : 4/7/2008<br>wwang : 2/27/2008<br>mgross : 2/7/2008<br>terry : 2/7/2008<br>wwang : 11/16/2007<br>ckniffin : 10/29/2007<br>alopez : 9/25/2007<br>terry : 9/20/2007<br>carol : 8/17/2007<br>ckniffin : 7/17/2007<br>wwang : 6/13/2007<br>wwang : 4/30/2007<br>wwang : 4/17/2007<br>alopez : 4/16/2007<br>alopez : 4/13/2007<br>terry : 4/5/2007<br>wwang : 3/14/2007<br>terry : 3/13/2007<br>wwang : 12/27/2006<br>ckniffin : 12/18/2006<br>wwang : 7/31/2006<br>ckniffin : 7/11/2006<br>carol : 6/9/2006<br>wwang : 5/31/2006<br>terry : 5/24/2006<br>alopez : 5/1/2006<br>alopez : 5/1/2006<br>terry : 4/27/2006<br>wwang : 4/6/2006<br>terry : 4/6/2006<br>carol : 4/6/2006<br>ckniffin : 2/8/2006<br>alopez : 2/3/2006<br>wwang : 12/7/2005<br>terry : 12/7/2005<br>alopez : 11/29/2005<br>terry : 11/17/2005<br>wwang : 10/27/2005<br>terry : 10/25/2005<br>carol : 9/14/2005<br>terry : 9/13/2005<br>carol : 9/1/2005<br>carol : 8/30/2005<br>carol : 8/30/2005<br>terry : 8/3/2005<br>tkritzer : 4/29/2005<br>terry : 4/26/2005<br>tkritzer : 1/13/2005<br>terry : 1/3/2005<br>carol : 7/9/2004<br>terry : 7/9/2004<br>terry : 6/25/2004<br>mgross : 4/21/2004<br>alopez : 2/16/2004<br>terry : 2/13/2004<br>tkritzer : 10/9/2003<br>terry : 10/7/2003<br>tkritzer : 8/26/2003<br>terry : 8/25/2003<br>mgross : 8/12/2003<br>terry : 8/12/2003<br>tkritzer : 5/2/2003<br>terry : 4/28/2003<br>alopez : 4/22/2003<br>terry : 4/22/2003<br>tkritzer : 1/3/2003<br>alopez : 12/12/2002<br>tkritzer : 11/18/2002<br>alopez : 11/18/2002<br>tkritzer : 11/13/2002<br>terry : 11/7/2002<br>tkritzer : 8/15/2002<br>tkritzer : 8/14/2002<br>tkritzer : 8/13/2002<br>tkritzer : 8/9/2002<br>terry : 8/8/2002<br>carol : 2/28/2002<br>cwells : 2/27/2002<br>terry : 2/21/2002<br>carol : 1/31/2002<br>mcapotos : 1/22/2002<br>terry : 1/17/2002<br>mcapotos : 9/19/2001<br>mcapotos : 9/17/2001<br>mcapotos : 9/12/2001<br>mcapotos : 8/16/2001<br>mcapotos : 8/3/2001<br>terry : 8/1/2001<br>mcapotos : 6/29/2001<br>mcapotos : 6/28/2001<br>terry : 6/26/2001<br>mcapotos : 5/9/2001<br>mcapotos : 5/8/2001<br>mcapotos : 4/25/2001<br>terry : 4/17/2001<br>cwells : 1/25/2001<br>terry : 1/12/2001<br>carol : 1/8/2001<br>mcapotos : 11/13/2000<br>terry : 11/2/2000<br>alopez : 10/25/2000<br>mcapotos : 9/8/2000<br>mcapotos : 9/7/2000<br>terry : 9/1/2000<br>mgross : 6/7/2000<br>mcapotos : 5/4/2000<br>mcapotos : 5/3/2000<br>terry : 4/10/2000<br>terry : 11/30/1999<br>alopez : 11/15/1999<br>terry : 11/9/1999<br>carol : 9/21/1999<br>jlewis : 8/2/1999<br>jlewis : 8/2/1999<br>terry : 7/20/1999<br>alopez : 5/10/1999<br>terry : 4/26/1999<br>alopez : 4/20/1999<br>alopez : 4/19/1999<br>alopez : 4/19/1999<br>alopez : 4/19/1999<br>carol : 3/3/1999<br>mgross : 2/12/1999<br>mgross : 2/10/1999<br>terry : 2/5/1999<br>carol : 1/5/1999<br>dkim : 12/11/1998<br>alopez : 12/8/1998<br>terry : 11/16/1998<br>dkim : 10/13/1998<br>carol : 10/12/1998<br>terry : 10/8/1998<br>carol : 9/21/1998<br>terry : 9/17/1998<br>carol : 9/2/1998<br>terry : 9/1/1998<br>carol : 7/1/1998<br>carol : 6/26/1998<br>terry : 6/23/1998<br>terry : 6/19/1998<br>carol : 6/12/1998<br>terry : 6/11/1998<br>alopez : 5/14/1998<br>psherman : 4/15/1998<br>alopez : 4/1/1998<br>alopez : 3/25/1998<br>terry : 3/17/1998<br>alopez : 12/5/1997<br>alopez : 12/3/1997<br>alopez : 11/25/1997<br>terry : 11/20/1997<br>jenny : 10/21/1997<br>terry : 10/14/1997<br>alopez : 7/30/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 6/2/1997<br>mark : 2/28/1997<br>terry : 2/26/1997<br>mark : 2/17/1997<br>terry : 2/11/1997<br>terry : 1/31/1997<br>mark : 1/31/1997<br>mark : 1/31/1997<br>jamie : 1/21/1997<br>terry : 1/15/1997<br>jenny : 1/7/1997<br>mark : 12/26/1996<br>mark : 8/27/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>mark : 8/7/1996<br>terry : 8/6/1996<br>terry : 8/2/1996<br>terry : 5/3/1996<br>carol : 4/26/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 3/3/1996<br>terry : 2/27/1996<br>mark : 1/10/1996<br>mark : 1/4/1996<br>mark : 9/7/1995<br>carol : 3/2/1995<br>terry : 2/13/1995<br>jason : 7/1/1994<br>carol : 6/23/1992<br>supermim : 3/16/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 176943
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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FIBROBLAST GROWTH FACTOR RECEPTOR 2; FGFR2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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FGF RECEPTOR<br />
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PROTEIN TYROSINE KINASE, RECEPTOR-LIKE, 14; TK14
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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KERATINOCYTE GROWTH FACTOR RECEPTOR, INCLUDED; KGFR, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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BEK, MOUSE, HOMOLOG OF, INCLUDED<br />
|
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FIBROBLAST GROWTH FACTOR RECEPTOR BEK, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FGFR2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 205258009, 62964007, 703528008, 70410008, 709105005, 83015004;
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<strong>ICD10CM:</strong> Q87.0;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 10q26.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:121,478,330-121,598,458 </span>
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
|
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<th>
|
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Phenotype
|
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</th>
|
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<th>
|
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Phenotype <br /> MIM number
|
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</th>
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<th>
|
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
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<td rowspan="14">
|
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<span class="mim-font">
|
|
10q26.13
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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?Scaphocephaly, maxillary retrusion, and impaired intellectual development
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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609579
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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207410
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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<tr>
|
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<td>
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<span class="mim-font">
|
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Apert syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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101200
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Autosomal dominant
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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<tr>
|
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<td>
|
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<span class="mim-font">
|
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Beare-Stevenson cutis gyrata syndrome
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
123790
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Bent bone dysplasia syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614592
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Craniofacial-skeletal-dermatologic dysplasia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
101600
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Craniosynostosis, nonspecific
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Crouzon syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
123500
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Gastric cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613659
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Jackson-Weiss syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
123150
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
LADD syndrome 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
149730
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pfeiffer syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
101600
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Saethre-Chotzen syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
101400
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Scaphocephaly and Axenfeld-Rieger anomaly
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Houssaint et al. (1990) isolated a gene encoding a putative receptor-like protein-tyrosine kinase, which the authors called TK14, from a human tumor cDNA library. The deduced amino acid sequence was closely related to that of the mouse protein bek (bacterially expressed kinase), and more distantly related to the sequences of a chicken basic fibroblast growth factor receptor (73% sequence homology) and its presumed human equivalent, the FLG protein (136350). Overexpression of the TK14 protein by transfection of COS-1 cells led to the appearance of new cell-surface binding sites for both acidic and basic fibroblast growth factors. Dionne et al. (1990) also cloned a complete cDNA for the human bek homolog (symbolized FGFR2). </p><p>Keratinocyte growth factor (148180) has potent mitogenic activity for a wide variety of epithelial cells but lacks detectable activity on fibroblasts or endothelial cells. This synthesis by stromal fibroblasts in a large number of epithelial tissues suggests that KGF is an important paracrine mediator of normal epithelial cell proliferation. Furthermore, studies indicated specific KGF binding to keratinocytes but not fibroblasts. Miki et al. (1991) devised an expression cloning strategy to isolate cDNA for the keratinocyte growth factor receptor. The 4.2-kb cDNA was shown to encode a predicted membrane-spanning tyrosine kinase related to, but distinct from, the basic FGF receptor. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. They have a similar protein structure, with 3 immunoglobulin-like domains in the extracellular region, a single membrane spanning segment, and a cytoplasmic tyrosine kinase domain. The other fibroblast growth factor receptors that have been identified are FGFR1 (136350); FGFR3 (134934), which is mutant in achondroplasia (100800); and FGFR4 (134935). Sequence analysis of the 4.5-kb human FGFR2 gene shows an open reading frame encoding the typical membrane-spanning, tyrosine kinase receptor structure of the FGFR gene family. Two alternative gene products have been characterized: KGFR and BEK. These 2 isoforms are identical except for a 49-amino acid sequence spanning the second half of the third Ig loop in the extracellular region. This local diversity is due to the presence of alternative exons within FGFR2, exon B being expressed in the BEK product and exon K26 in KGFR. Control of these alternative splice sites is thought to involve transacting factors (Gilbert et al., 1993). The variation in expressed gene product is highly significant because the ligand-binding characteristics of KGFR and BEK are quite distinct. Furthermore, they have different patterns of expression in murine embryogenesis. Whereas KGFR appears to have a role in skin development, BEK is preferentially expressed in osteogenesis. BEK transcripts are concentrated in the frontal bones, maxilla, mandibula, and ossicles of the middle ear. </p><p>Wilkie et al. (1995) provided a useful resume of the 4 different systems that have been used for numbering exons in the FGFR genes and the cDNA nucleotide numbering system. </p><p>Moore et al. (2004) studied the role of FGF and ephrin signaling in retina development in the frog. Activation of Fgfr2 signaling before gastrulation repressed cellular movements in the presumptive anterior neural plate and prevented normal retinal progenitor cells from adopting retinal fates. Ephrin B1 (300035) signaling during gastrulation was required for retinal progenitors to move into the eye field, and this movement could be modified by activating the FGF pathway. Moore et al. (2004) concluded that FGF modulation of ephrin signaling is important for establishing the bona fide retinal progenitors in the anterior neural plate. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
To elucidate the structural determinants governing specificity in FGF signaling, Plotnikov et al. (2000) determined the crystal structures of FGF1 (131220) and FGF2 (134920) complexed with the immunoglobulin-like ligand-binding domains 2 and 3 (D2 and D3) of FGFR1 and FGFR2, respectively. They found that highly conserved FGF-D2 and FGF-linker (between D2 and D3) interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and 2 loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing. </p><p>Pellegrini et al. (2000) reported the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide. The complex is assembled around a central heparin molecule linking 2 FGF1 ligands into a dimer that bridges between 2 receptor chains. The asymmetric heparin binding involves contacts with both FGF1 molecules but only one receptor chain. The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulfate in FGF signaling. </p><p>FGF-FGFR binding specificity is essential for mammalian development and is regulated primarily by 2 alternatively spliced exons, IIIb (b) and IIIc (c), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Yeh et al. (2003) reported the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions of FGF10 and 2 b-specific loops in D3 revealed the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirmed the importance of the observed contacts for FGF10 biologic activity. FGF10 binding induced a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. Yeh et al. (2003) proposed that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Mattei et al. (1991) used a 2.3-kb cDNA probe from the human BEK fibroblast growth factor receptor to determine localization of the gene on chromosome 10q26 by in situ hybridization. Dionne et al. (1992) assigned the BEK gene to chromosome 10 by applying PCR techniques to DNAs from a panel of human/rodent somatic cell hybrids. They further localized the gene to chromosome 10q25.3-q26 by in situ hybridization. Using an interspecific backcross mapping panel, Avraham et al. (1994) mapped the murine equivalent to chromosome 7. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Because of the clear importance of BEK expression in osteogenesis and the localization of FGFR2 to the same chromosomal region as the mutation responsible for Crouzon syndrome (CFD1; 123500), FGFR2 became a candidate gene for the clinical disorder. Reardon et al. (1994) found SSCP variations in the B exon of FGFR2 in 9 unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in 3 unrelated multigeneration families. In 4 sporadic cases, the unaffected parents did not have SSCP variation. Direct sequencing revealed specific mutations in the B exon in all 9 sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in 5 patients. In only 9 out of 20 patients with Crouzon syndrome did Reardon et al. (1994) find mutations in the FGFR2 gene. There was, however, no evidence for genetic heterogeneity either in a previously published linkage report (Preston et al., 1994) or in the new data. It was thought likely that mutations in other areas of the FGFR2 gene were responsible for the cases yet to be explained. </p><p>Jabs et al. (1994) demonstrated mutations in the FGFR2 gene in patients with Crouzon syndrome as well as in patients with Jackson-Weiss syndrome (JWS; 123150). </p><p>Wilkie et al. (1995) found mutations in the FGFR2 gene in Apert syndrome (101200). In all 40 unrelated cases of Apert syndrome studied, they identified specific missense substitutions involving adjacent amino acids (ser252-to-trp, 176943.0010 and pro253-to-arg, 176943.0011) in the linker between the second and third extracellular immunoglobulin (Ig) domains of FGFR2. The first of these mutations was caused by a C-to-G transversion at position 934 of the cDNA. The second was caused by a C-to-G transversion at position 937. Jabs et al. (1994) referred to these as the type 1 and type 2 mutations, respectively. The 934C-G mutation arose in a CpG dinucleotide, whereas the 937C-G mutation did not. The fact that they did not observe any 934C-T mutations (ser252-to-leu) suggested that this would give a phenotype different from that of Apert syndrome. Wilkie et al. (1995) found the type 1 mutation in 25 of the patients and the type 2 mutation in 15. In 3 patients, the parental origin of new mutations was established to be the father. </p><p>In a larger series of 118 unrelated cases of Apert syndrome studied in Oxford, Moloney et al. (1996) found that 74 had the 934C-G mutation and 44 had the 937C-G mutation. Combined with the cases reported by Park et al. (1995), the total experience indicated that 108 of 166 cases (65%) were of the 934C-G type, 57 of 166 cases (34%) were of the 937C-G type, and 1 case observed by Park et al. (1995) was of unknown mutational basis. Wilkie (1996) observed paternal age effect with both Apert mutations in 54 informative families; the mutation was of paternal origin in all cases. Limb malformation seemed to be more severe in the 937C-G mutation; cleft palate was more often present, and craniofacial abnormality was in general more severe with the 934C-G mutation (Wilkie, 1996). Indeed, the severe craniofacial abnormality and cleft palate in association with milder involvement of the hands gave rise to the designation of Vogt cephalodactyly or Apert-Crouzon disease for the condition in the cases described by Vogt (1933) combining the hand and foot malformations characteristic of Apert disease with the facial characteristics of Crouzon disease; see 101200. </p><p>Lajeunie et al. (1995) and Rutland et al. (1995) found mutations in the FGFR2 gene in some patients with Pfeiffer syndrome (101600). In the instance of some mutations, the disorder was Pfeiffer syndrome in some families and Crouzon syndrome in others. Thus, mutations in the FGFR2 gene may result in any one of several different phenotypes. The clinical criteria of Pfeiffer syndrome, particularly interphalangeal ankylosis, are thought to be distinctive (Lajeunie et al., 1995). There is no confusion of Pfeiffer syndrome with Crouzon syndrome, in which no hand anomalies and occasional radial-ulnar synostosis have been reported, or with Jackson-Weiss syndrome, which includes a tarsal-metatarsal coalescence and a medial deviation of broad great toes. The occurrence of different phenotypes with the same mutation may reflect the presence on the same chromosome of a particular change elsewhere in the gene. This would be comparable to the asp178-to-asn mutation in the prion protein gene (176640), which results in familial fatal insomnia (600072) when the amino acid at position 129 is methionine, and in Creutzfeldt-Jakob disease (123400) when the amino acid at position 129 is valine. Mulvihill (1995) commented that in statistical parlance, some clinical diagnoses of syndromes of multiple malformations are more like confidence intervals than point estimates. He suggested further that permutation may be a better term than mutation. With over 100 craniosynostosis syndromes, 9 fibroblast growth factors, and 4 receptors for them, each with many overlapping and homologous regions, combination and permutation may lead to the inevitable failure of the one mutation-one disease model. </p><p>In a study of 39 unrelated patients with Crouzon, Jackson-Weiss, or Pfeiffer syndrome, Meyers et al. (1996) identified 11 mutations in exon IIIa or exon IIIc in 17 patients. Although previous studies had identified mutations in exon IIIa only in Crouzon syndrome patients, Meyers et al. (1996) identified them in Jackson-Weiss and Pfeiffer syndrome patients as well. Steinberger et al. (1996) identified previously unrecognized mutations in each of 3 patients with Crouzon syndrome: a deletion, a duplication, and a point mutation. </p><p>Steinberger et al. (1996) described an FGFR2 mutation (176943.0006) in a large family with autosomal dominant craniosynostosis with marked phenotypic variation and with clinical manifestations that were not classifiable as Apert, Crouzon, Pfeiffer, or Jackson-Weiss syndromes. The mutation detected in the family described by Steinberger et al. (1996) is identical to that described in a family with Crouzon syndrome by Reardon et al. (1994) and by Jabs et al. (1994). </p><p>Oldridge et al. (1997) stated that recurrent mutations of a serine-proline dipeptide (either ser252 to trp or pro253 to arg) had been identified in more than 160 unrelated individuals with Apert syndrome. They identified 3 novel mutations of this dipeptide associated with distinct phenotypes. The substitution ser252leu was demonstrated in a boy with mild Crouzon syndrome and was also present in 3 clinically normal members of his family. A CG-to-TT mutation that predicted a ser252-to-phe substitution (176943.0017) resulted in a phenotype consistent with Apert syndrome. Finally, a CGC-to-TCT mutation that predicted a double amino acid substitution (ser252 to phe and pro253 to ser; 176943.0018) caused a Pfeiffer syndrome variant with mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The observation that the ser252-to-phe mutation causes Apert syndrome, whereas the other single or double substitutions are associated with milder or normal phenotypes, highlighted the exquisitely specific molecular pathogenesis of the limb and craniofacial abnormalities associated with Apert syndrome. Oldridge et al. (1997) stated that the substitution ser252 to phe was the first noncanonical mutation to be identified in Apert syndrome, its rarity being explained by the requirement for 2 residues of the serine codon to be mutated. The authors noted that they had previously demonstrated exclusive paternal origin of mutation in Apert syndrome in 57 of 57 cases, and suggested that the high apparent rates for several FGFR mutations could arise by a selective advantage conferred to the mutated male germ cell (Moloney et al., 1996). Consistent with this, there is evidence that the FGF/FGFR signaling pathway plays an important role in the initiation and maintenance of spermatogenesis (Van Dissel-Emiliani et al., 1996). </p><p>Goriely et al. (2003) developed a sensitive method to quantify substitutions at nucleotide 755 of the FGFR2 gene, which lead to mutations in codon 252, in sperm. They measured mutation levels in samples from blood of 11 healthy individuals, sperm from 99 healthy men without a family history of Apert syndrome, and sperm from 6 unaffected fathers of children with Apert syndrome caused by the 755C-G mutation. Only low levels (less than 10(-5)) of all mutations were found in blood, which excluded the possibility that higher levels in sperm were caused by contamination or PCR artifacts. In sperm, the level of 755C-A never exceeded 6.3 x 10(-6) and showed no paternal age effects (r of -0.06; p of 0.71), but both 755C-G and 755C-T reached high levels (maxima of 1.6 x 10(-4) and 1.4 x 10(-4), respectively) that were positively correlated with donor age. The average level of 755C-G was 1.66-fold higher than that of 755C-T, which was statistically significant. Levels of the 755C-G mutation in the sperm of fathers of Apert syndrome children were also within the envelope of normal values, indicating that these men were sampled from the general population and had a very low risk of fathering another affected child. Further analyses led Goriely et al. (2003) to conclude that the major factor underlying the paternal age effect is not the accumulation of replication errors or insufficient repair processes, but positive selection of infrequent mutations acting over the course of time. They stated that the constancy of FGFR2 mutation levels over many months indicated that the mutations are present in spermatogonia with stem cell-like properties. Goriely et al. (2003) proposed that these FGFR2 mutations, although harmful to embryonic development, are paradoxically enriched because they confer selective advantage to the spermatogonial cells in which they arise. </p><p>Glaser et al. (2003) studied the paternal age effect and the exclusive paternal origin of mutations reported in Apert syndrome. As the incidence of sporadic Apert syndrome births increases exponentially with paternal age, they hypothesized that the frequency of Apert syndrome mutations in sperm would also increase. They noted that 99% of sporadic cases of Apert syndrome are caused by 1 of 2 common mutations in the FGFR2 gene, S252W (176943.0010) or P253R (176943.0011), and developed allele-specific peptide nucleic acid PCR assays to determine the frequency of these 2 mutations. Analyzing sperm DNA from 148 men, aged 21 to 80 years, they showed that the number of sperm with mutations increased in the oldest age groups among men who did not have a child with Apert syndrome. These older men were also more likely to have both mutations in their sperm. However, this age-related increase in mutation frequency was not sufficient to explain the Apert syndrome birth frequency. In contrast, the mutation frequency observed in men who were younger and had children with Apert syndrome was significantly greater. The data suggested selection for sperm with specific mutations. Therefore, contributing factors to the paternal age effect may include selection and a higher number of mutant sperm in a subset of men ascertained because they had a child with Apert syndrome. No age-related increase in the frequency of these mutations was observed in leukocytes. Selection and/or quality control mechanisms, including DNA repair and apoptosis, may contribute to the cell type differences in mutation frequency. </p><p>In a study of sporadic cases of Crouzon syndrome and Pfeiffer syndrome, Glaser et al. (2000) used 4 intragenic polymorphisms to screen a total of 41 families. Of these, 22 (11 for each syndrome) were informative. They found 11 different mutations in the 22 families. By molecular means they proved that the origin of these different mutations was paternal in all informative cases analyzed. Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34.50 +/- 7.65 years vs 30.45 +/- 1.28 years, P less than 0.01). The data extended previous information on advanced paternal age for sporadic FGFR2 mutations causing Apert syndrome and FGFR3 mutations causing achondroplasia. </p><p>In a screening of 14 patients with craniosynostosis syndromes known to be related to FGFR2, Hollway et al. (1997) looked for mutations in exons IIIa and IIIc of FGFR2. They found 9 mutations, 8 of which had previously been reported. One patient with Pfeiffer syndrome was found to have a novel mutation. </p><p>Tartaglia et al. (1997) reported a de novo G-to-C transversion in exon IIIa of the FGFR2 gene, detected in a patient with severe Pfeiffer clinical features (176943.0019). Missense mutations at codon 290 of FGFR2 had been reported previously in Crouzon syndrome, but not in Pfeiffer syndrome. Codon 290 appears to be a mutation hotspot in the FGFR2 gene. A trp290-to-arg substitution results in classic Crouzon syndrome (Meyers et al., 1996), whereas trp290 to gly results in an atypically mild form of Crouzon syndrome (Park et al., 1995). </p><p>Steinberger et al. (1998) reviewed the reported FGFR2 mutations associated with craniosynostoses and described 3 previously unrecognized mutations. They pointed out that the known mutations involved 5 distinct structural elements of the receptor. The changes within these elements affect receptor function by various mechanisms, including altered dimerization, truncation, increased mobility between Ig domains, disintegration of IgIII, and alteration of the ligand-binding site. An erratum for the article by Steinberger et al. (1998) included a new Table 2, which listed FGFR2 mutations found in craniosynostoses. </p><p>Apert syndrome results from specific mutations at 2 adjacent residues of the FGFR2 gene, ser252 to trp (176943.0010) and pro253 to arg (176943.0011), predicted to lie in the linker region between IgII and IgIII regions of the portions of the FGFR2 ligand-binding domain. Anderson et al. (1998) analyzed the interaction of FGF ligands with wildtype and Apert-type mutant FGFR2 ectodomains in solution. Wildtype and Apert-type receptors form a complex with FGF ligands with a stoichiometry of 2:2 (ligand:receptor). The kinetics and specificity of ligand binding to wildtype and Apert mutant receptors were analyzed using surface plasmon resonance techniques. Anderson et al. (1998) found that Apert mutations, compared with wildtype, exhibited a selective decrease in the dissociation kinetics of FGF2, but not of other FGF ligands examined. In contrast, the substitution ser252 to leu in FGFR2, previously observed in several asymptomatic individuals, exhibited wildtype kinetics. These findings indicate that Apert syndrome arises as a result of increased affinity of mutant receptors for specific FGF ligands which leads to activation of signaling under conditions where availability of ligand is limiting. </p><p>Apert syndrome is commonly accompanied by acne. Munro and Wilkie (1998), cognizant of this and with unifying insight, studied a patient who was well except for acne, which was present in the pattern described by Blaschko in the 19th century (Jackson, 1976). In this pattern, abnormality of the skin is limited to a linear or whirled pattern. Commonly misinterpreted as dermatomal, the pattern, and therefore the mechanism, is quite distinct. This was interpreted by Shuster (1978) as representing the clonal pattern of movement of cells during development. Munro and Wilkie (1998) reasoned that if a germline defect in FGFR2 causes acne in the context of Apert syndrome, a mutation confined to epidermal cells (because it had arisen during development) might produce acne in the pattern described by Blaschko. They showed that one of the common FGFR2 mutations in Apert syndrome, a ser252-to-trp substitution, is present in the abnormal but not the normal skin. </p><p>Passos-Bueno et al. (1999) provided an up-to-date listing of the mutations in FGFR1, FGFR2, and FGFR3 associated with distinct clinical entities, including achondroplasia (100800), hypochondroplasia (146000), platyspondylic lethal skeletal dysplasia (see 151210 and 187600), thanatophoric dysplasia (see 187600 and 187601), Antley-Bixler syndrome (207410), Apert syndrome (101200), Beare-Stevenson cutis gyrata syndrome (BSTVS; 123790), Crouzon syndrome (123500), Jackson-Weiss syndrome (123150), Pfeiffer syndrome (101600), and Saethre-Chotzen syndrome (101400). </p><p>Yu et al. (2000) demonstrated that the mutations in 2 adjacent amino acid residues that cause Apert syndrome, S252W (176943.0010) and P253R (176943.0011), break one of the cardinal rules governing ligand specificity of FGFR2. They are located in the highly conserved region linking Ig-like domains II and III of FGFR2. Yu et al. (2000) showed that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated by the mesenchymally expressed ligands FGF7 (148180) or FGF10 (602115) and the epithelial splice form of FGFR2 (FGFR2b) to be activated by FGF2 (134920), FGF6 (134921), and FGF9 (600921). The data demonstrated loss of ligand specificity of FGFR2 with retained ligand dependence for receptor activation. The data suggested that the severe phenotypes of Apert syndrome likely result from ectopic ligand-dependent activation of FGFR2. </p><p>Of 260 cases of Apert syndrome studied by Oldridge et al. (1999), 2 did not have missense mutations in the FGFR2 gene but rather de novo Alu insertions upstream or within exon 9 of FGFR2 (176943.0025). </p><p>To elucidate the mechanism by which 2 activating mutations in FGFR2, ser252 to trp (176943.0010) and pro253 to arg (176943.0011), cause Apert syndrome, Ibrahimi et al. (2001) determined the crystal structures of these 2 FGFR2 mutants in complex with fibroblast growth factor-2 (FGF2). These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and the sequence alignment of the FGF family, they proposed that the pro253-to-arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the ser252-to-trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of Apert syndrome mutations on FGF binding. The distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among Apert syndrome patients. For example, patients with the ser252-to-trp mutation present more frequently with cleft palate, whereas patients with the pro253-to-arg mutation exhibit more severe syndactyly (Slaney et al., 1996; Lajeunie et al., 1999). </p><p>Most mutations in Crouzon, Pfeiffer, and Apert syndromes occur in the extracellular third Ig-like domain and adjacent linker regions (exons IIIa and IIIc) of the FGFR2 gene. Wong et al. (2001) pointed out that an error in molecular diagnosis of craniosynostosis syndrome can result from a single nucleotide polymorphism (SNP) located in the commonly used primer site. They reported patients who appeared to be homozygous for particular mutations because of this polymorphism, which they determined to have a frequency of 3% in the general population. </p><p>To study the apparent clustering of mutations in the IgIII region of FGFR2, Kan et al. (2002) screened 259 patients with craniosynostosis in whom mutations in other genes, such as FGFR1, FGFR3, and TWIST1 (601622), had been excluded. Unbiased estimates of the mutation distribution were permitted because part of the screen was a cohort-based study. Although most of the FGFR2 mutations in the cohort sample (61 of 62) were localized to the IIIa and IIIc exons, Kan et al. (2002) identified mutations in 7 additional exons, including 6 distinct mutations in the tyrosine kinase region and a single mutation in the IgII domain. Most of the patients with atypical mutations had diagnoses of Pfeiffer syndrome or Crouzon syndrome. Overall, FGFR2 mutations were present in 9.8% of patients with craniosynostosis who were included in the prospectively ascertained sample, but no mutations were found in association with isolated fusion of the metopic or sagittal sutures. Kan et al. (2002) concluded that the spectrum of FGFR2 mutations causing craniosynostosis is wider than previously recognized but that the IgIIIa/IIIc region represents a genuine mutation hotspot. </p><p>In an extensive review of the genetics of craniofacial development and malformation, Wilkie and Morriss-Kay (2001) provided a useful diagram of the molecular pathways in cranial suture development with a listing of all craniofacial disorders caused by mutations in the corresponding genes. Four proteins were indicated as having strong evidence for existing in the pathway, with successive downstream targets as follows: TWIST--FGFR2--FGFR1--CBFA1 (600211). </p><p>Warren et al. (2003) demonstrated that Noggin (602991) is expressed postnatally in the suture mesenchyme of patent, but not of fusing, cranial sutures, and that Noggin expression is suppressed by FGF2 and syndromic FGFR signaling. Warren et al. (2003) studied the effects of Apert (S252W; 176943.0010) and Crouzon (see C342Y; 176943.0001) syndrome Fgfr2 gain-of-function mutations on Noggin production in dural cell and osteoblast cultures. Both Apert and Crouzon syndrome Fgfr2 mutants markedly downregulated Noggin protein production in sagittal dura mater. The Apert and Crouzon Fgfr2 constructs also downregulated Bmp4 (112262)-induced Noggin expression in calvarial osteoblasts. Because both Apert and Crouzon syndrome Fgfr gain-of-function mutations promote pathologic suture fusion, Warren et al. (2003) concluded that their findings provide an important link between the murine models and the gain-of-function Fgfr mutations associated with syndromic Fgfr-mediated craniosynostoses. Warren et al. (2003) also showed that forced expression of Noggin maintained posterior frontal suture patency in mice. They suggested that since ectopic Noggin expression prevented the fusion of mouse posterior frontal sutures, it is possible that therapeutic Noggin could be exploited to control postnatal skeletal development. </p><p>Zankl et al. (2004) noted that mutations in the FGFR2 gene cause a variety of craniosynostosis syndromes, and that most mutations had been found in either exon IIIa or IIIc or in the intronic sequence preceding exon IIIc. Mutations outside this hotspot were uncommon and the few identified mutations demonstrated wide clinical variability. </p><p>In affected members of a family with mild features of Crouzon syndrome, Kan et al. (2004) identified heterozygosity for a splice site mutation in the FGFR2 gene (176943.0038). Although both A and G are consensus nucleotides at the +3 position of the 5-prime splice site, oligonucleotide hybridization experiments revealed that the A-G substitution causes a switch to the use of a known cryptic 5-prime splice site (see 176943.0006) within the upstream exon IIIc. </p><p>Ibrahimi et al. (2004) analyzed the effect of the canonic Apert syndrome mutations (176943.0010, 176943.0011), the D321A Pfeiffer syndrome mutation (176943.0039), and the S252L/A315S (176943.0028) double mutation on FGFR2 ligand binding affinity and specificity using surface plasmon resonance. Both Apert syndrome mutations and the D321A Pfeiffer syndrome mutation, but not the S252L/A315S double mutation, increased the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. All 4 pathogenic mutations also violated FGFR2c ligand binding specificity and enabled this receptor to bind FGF10. The authors proposed that an increase in mutant FGFR2c binding to multiple FGFs may result in craniosynostosis, whereas binding of mutant FGFR2c to FGF10 may result in severe limb pathology. Structural and biophysical analyses showed that Apert syndrome mutations in FGFR2b also enhanced and violated FGFR2b ligand binding affinity and specificity, respectively. Ibrahimi et al. (2004) suggested that elevated Apert syndrome mutant FGFR2b signaling may account for the dermatologic manifestations of Apert syndrome. </p><p>McGillivray et al. (2005) identified a mutation in the FGFR2 gene (176943.0034) in a 3-generation family with a form of craniosynostosis characterized by scaphocephaly, maxillary retrusion, and impaired intellectual development (609579). </p><p>In a boy with scaphocephaly and an Axenfeld-Rieger anomaly, McCann et al. (2005) identified heterozygosity for an ala344-to-ala mutation in the FGFR2 gene (A344A; 176943.0006). The authors noted that severe ocular anterior chamber dysgenesis (Peters anomaly) had been previously described in 3 patients with severe craniosynostosis syndromes (see 176943.0024 and Okajima et al., 1999), and concluded that the FGFR2 gene has a role in anterior chamber embryogenesis. </p><p>Lajeunie et al. (2006) screened 131 patients with clinical features of Apert, Crouzon, Pfeiffer, or Jackson-Weiss syndromes and identified mutations in FGFR1, FGFR2, or FGFR3 in 125 patients. The authors noted that 2 FGFR2 mutations creating cysteine residues, W290C (176943.0019) and Y340C, caused severe forms of Pfeiffer syndrome, whereas conversion of the same residues into another amino acid, W290R/W290G (176943.0021/176943.0022) or Y340H (176943.0004), resulted in the Crouzon phenotype exclusively. Lajeunie et al. (2006) concluded that the mutation spectrum of FGFR2 mutations in Crouzon and Pfeiffer syndromes is wider than originally thought, and that despite some overlap, Crouzon and Pfeiffer syndromes are preferentially accounted for by 2 distinct sets of FGFR2 mutations. </p><p>Autosomal dominant lacrimoauriculodentodigital (LADD) syndrome (LADD1; 149730) is a multiple congenital anomaly mainly affecting lacrimal glands and ducts, salivary glands and ducts, ears, teeth, and distal limb segments. Rohmann et al. (2006) found mutations in the FGFR2 gene in 3 families and a sporadic case of LADD syndrome. In a Dutch and an English LADD family they found the same heterozygous missense mutation, A648T (176943.0035), in affected members. They showed that the mutation probably originated independently in these families, as there was no common founder haplotype. In another family a heterozygous 3-bp deletion was found (176943.0036). In a sporadic case of LADD syndrome a de novo missense mutation, A628T (176943.0037), was identified. </p><p>In a sperm study of 97 men aged 22 to 80 years, Wyrobek et al. (2006) found associations between increased age and genomic defects as measured by the DNA fragmentation index and increased age and the FGFR3 1138G-A mutation (134934.0001) without evidence for an age threshold. However, there was no association between age and frequency of sperm with immature chromatin, aneuploidies/diploidies, FGFR2 mutations causing Apert syndrome (i.e., 176943.0010), or sex ratio. </p><p>Riley et al. (2007) analyzed 12 genes involved in the fibroblast growth factor signaling pathway in nonsyndromic cleft lip or palate families and identified 7 likely disease-causing mutations in which structural analysis predicted functional impairment in the FGFR1, FGFR2, FGFR3, and FGF8 (600483) genes. Riley et al. (2007) suggested that the FGF signaling pathway may contribute to as much as 3 to 5% of nonsyndromic cleft lip or palate. </p><p>Miraoui et al. (2010) used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutation in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR (131550) and PDGFR-alpha (173490) expression was abnormally increased in human Apert calvaria osteoblasts compared with wildtype cells. Pharmacologic inhibition of EGFR and PDGFR reduced the pathologic upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Activated FGFR2 enhanced EGFR and PDGFR-alpha mRNA expression via activation of PKC-alpha (176960)-dependent AP1 (see JUN, 165160) transcriptional activity. The increased EGFR protein expression in Apert osteoblasts resulted in part from a posttranscriptional mechanism involving increased Sprouty2 (602466)-Cbl (165360) interaction, leading to Cbl sequestration and reduced EGFR ubiquitination. </p><p>Merrill et al. (2012) analyzed 6 candidate genes in 3 female fetuses and 1 male fetus with a perinatal lethal bent bone dysplasia syndrome (BBDS1; 614592) and identified heterozygosity for the same de novo missense mutation in the FGFR2 gene in 3 of them (M391R; 176943.0043), with a different heterozygous FGFR2 mutation detected in the remaining fetus (Y381D; 176943.0044). Merrill et al. (2012) stated that the clinical and genetic findings of the 4 affected individuals constituted a distinct disorder that they designated 'bent bone dysplasia (BBD)-FGFR2 type.' </p><p>In a cohort of 182 Spanish probands with craniosynostosis, Paumard-Hernandez et al. (2015) screened 5 craniosynostosis-associated genes, including FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 (300035). The 2 characteristic Apert syndrome-associated FGFR2 mutations, S252W and P253R, were detected in 23 (85%) of 27 patients with a clinical diagnosis of Apert syndrome. The authors noted that the 4 remaining patients were referred for 'possible' Apert syndrome and likely had a different type of craniosynostosis. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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Jang et al. (2001) identified a heterozygous somatic mutation in the FGFR2 gene (S267P; 176943.0029) in gastric cancer tissue (137215). The mutation was an activating mutation. </p><p>Pollock et al. (2007) identified 11 different somatic FGFR2 mutations (see, e.g., 176943.0010 and 176943.0015) in 3 (30%) of 10 endometrial cancer (608089) cell lines and in 19 (10%) of 187 primary endometrial carcinomas. The majority of the mutations were identical to germline activating mutations that cause skeletal dysplasias. There was no apparent correlation between FGFR2 mutation and overall survival. </p><p>Dutt et al. (2008) found FGFR2 mutations in 15 (12.3%) of 122 primary endometrial carcinomas, as well as in 2 of 42 lung squamous cell carcinomas and in 2 of 46 cervical carcinomas. Many of the mutations were identical to those associated with congenital craniofacial developmental disorders. Ectopic expression of the mutations in mouse fibroblasts demonstrated constitutive activation and oncogenicity, and inhibition of FGFR2 kinase activity in endometrial cell lines bearing such FGFR2 mutations inhibited transformation and survival. </p><p>Ota et al. (2009) showed that birth defect and cancer-associated FGFR2 mutants promoted DNA-damage signaling and p53 (191170)-dependent senescence in primary mouse and human cells. Senescence promoted by FGFR mutants was associated with downregulation of c-Myc (190080) and forced expression of c-Myc facilitated senescence escape. Whereas c-Myc expression facilitated senescence bypass, mutant FGFR2 signaling suppressed c-Myc-dependent apoptosis and led to oncogenic transformation. Cells transformed by coexpression of a constitutively activated FGFR2 mutant plus c-Myc appeared to become highly addicted to FGFR-dependent prosurvival activities, as small molecule inhibition of FGFR signaling resulted in robust p53-dependent apoptosis. Ota et al. (2009) suggested that senescence-promoting activities of mutant FGFRs may normally limit their oncogenic potential and may be relevant to their ability to disrupt morphogenesis and cause birth defects. </p><p><strong><em>Association with Breast Cancer</em></strong></p><p>
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Easton et al. (2007) identified a G/A SNP in intron 2 of the FGFR2 gene (rs2981582) that was significantly (p = 2 x 10(-76)) associated with familial breast cancer (114480) in a 3-stage genomewide association study of 22,848 cases from 22 studies. Easton et al. (2007) found that the allele was very common in the U.K. population and thus unlikely to confer increased disease risk individually. However, in combination with other susceptibility alleles, the SNP may become clinically significant. </p><p>Hunter et al. (2007) identified a SNP (rs1219648) in intron 2 of the FGFR2 gene that was significantly (p = 1 x 10(-10)) associated with sporadic postmenopausal breast cancer in a 2-stage genomewide association study of 1,145 and 1,776 affected individuals of European ancestry, respectively. The pooled odds ratios were 1.20 for heterozygotes and 1.64 for homozygotes. </p><p>In a sample of 10,358 carriers of BRCA1 (113705) or BRCA2 (600185) gene mutations from 23 studies, Antoniou et al. (2008) observed a significant association between breast cancer and the minor allele of G/A SNP in intron 2 (rs2981582; hazard ratio of 1.32; p-trend = 1.7 x 10(-8)) in BRCA2 carriers, but not in BRCA1 carriers. The authors concluded that this locus interacts multiplicatively on breast cancer risk in BRCA2 mutation carriers. </p><p>Udler et al. (2009) evaluated 8 candidate-causal FGFR2 SNPs in 1,253 African American invasive breast cancer cases and 1,245 controls. A significant association with breast cancer risk was found with rs2981578 (unadjusted per-allele odds ratio = 1.2, P-trend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. Genotype data from the African American studies were analyzed jointly with data from European (7,196 cases and 7,275 controls) and Asian (3,901 cases and 3,205 controls) studies. In the combined analysis, rs2981578 was the most strongly associated. Analysis of DNase I hypersensitive sites indicated that only 2 of these mapped to highly accessible chromatin, one of which, rs2981578, had previously been implicated in upregulating FGFR2 expression. </p><p>Meyer et al. (2013) conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. Meyer et al. (2013) identified 3 statistically independent risk signals within the 10q26 FGFR2 locus. Within risk signals 1 and 3, genetic analysis identified 5 and 2 variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and EMSA to study protein-DNA binding, Meyer et al. (2013) identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 (602294) preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit estrogen receptor-alpha (133430) to this site in an allele-specific manner, whereas E2F1 (189971) preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5-phosphorylated RNA polymerase II (see 180660), suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region Meyer et al. (2013) concluded that a role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen receptor-positive disease. </p>
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<p>Arman et al. (1998) found that disruption of the FGFR2 gene in mice resulted in a recessive embryonic lethal mutation. Preimplantation development was normal until the blastocyst stage. Homozygous mutant embryos died a few hours after implantation at a random position in the uterine crypt, with collapsed yolk cavity. Other observations indicated that FGFR2 is required for early postimplantation development between implantation and the formation of the egg cylinder. Arman et al. (1998) suggested that FGFR2 contributes to the outgrowth, differentiation, and maintenance of the inner cell mass and raised the possibility that this activity is mediated by FGF4 (164980) signals transmitted by FGFR2. </p><p>Deng et al. (1997) showed by chimera experiments with homozygous mutant embryonic stem (ES) cells that Fgfr1 has a role in limb and central nervous system development. Involvement of Fgfr2 in limb outgrowth was indicated by a targeted mutation that displayed no limb buds but, because of placental insufficiency, did not survive beyond early limb outgrowth (Xu et al., 1998). Fgfr2 in the early embryo is expressed in the trophectoderm, and this extra-embryonic localization persists into mid- and late gestation, when Fgfr2 is also expressed in multiple developing organs. To gain insight into the later functions of Fgfr2, Arman et al. (1999) constructed fusion chimeras from homozygous mutant embryonic stem cells and wildtype tetraploid embryos. This allowed survival until term and revealed that Fgfr2 is required for both limb outgrowth and branching lung morphogenesis. The use of fusion chimeras demonstrated that early lethality was indeed because of trophectoderm defects and indicated that in the embryonic cell lineages Fgfr2 activity manifests in limb and lung development. Highly similar lung and limb phenotypes were detected in a loss-of-function mutation of Fgf10 (602115), a ligand of Fgfr2. It is likely, therefore, that whereas during early development Fgfr2 interacts with Fgf4, interactions between Fgf10 and Fgfr2 may be required in limb and lung development. </p><p>In Fgf10 -/-, Fgfr2b -/-, and Sonic hedgehog (SHH; 600725) -/- mice, which all exhibit cleft palate, Rice et al. (2004) showed that Shh is a downstream target of Fgf10/Fgfr2b signaling. Using BrdU staining, they demonstrated that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by the finding that cell proliferation was decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b -/- mice. Rice et al. (2004) concluded that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an FGF-SHH signaling network. </p><p>Mice deficient for fibroblast growth factor receptors show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, and profound defects in membranous and endochondral bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Hajihosseini et al. (2001) showed that heterozygotic abrogation of exon 9 of the Fgfr2 gene in mice caused a splicing switch resulting in a gain-of-function mutation. The consequences were neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. The phenotype was considered to have strong parallels to some Apert (101200) and Pfeiffer (101600) syndrome patients. </p><p>Eswarakumar et al. (2004) created transgenic mice expressing a gain-of-function mutation (C342Y; 176943.0001) in the Fgfr2 gene. Heterozygous mutant mice were viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 (166490) expression in the calvaria. Homozygous mutants displayed multiple joint fusions, cleft palate, and trachea and lung defects, and died shortly after birth. They showed enhanced Cbfa1 expression without significant change in chondrocyte-specific gene expression. Histomorphometric analysis and bone marrow stromal cell culture showed a significant increase of osteoblast progenitors with no change in osteoclastogenic cells. Chondrocyte proliferation was decreased in the skull base at embryonic day 14.5 but not later. Eswarakumar et al. (2004) concluded that the mutant phenotype, including craniosynostosis, is related to FGFR2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of FGFR2c with FGFR3 (134934) in the formation of the cartilage model for endochondral bone. </p><p>Eswarakumar et al. (2006) generated C342Y +/- mice and observed ocular proptosis, a rounded cranium, fusion of the coronal sutures, and a significantly shortened facial region in the mutant mice. Expression of the C342Y mutation in cis with L424A and R426A mutations of the juxtamembrane domain resulted in attenuation of signaling pathways by selectively uncoupling Frs2a (607743) and activated Fgfr2c, thus preventing premature fusion of sutures and resulting in normal skull development. Eswarakumar et al. (2006) also demonstrated that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevented premature fusion of sutures without adversely affecting the development of the skull. </p><p>Shukla et al. (2007) developed mice with conditional expression of Fgfr2 with the S252W (176943.0010) missense mutation. Mice carrying the activated form of Fgfr2-S252W showed malformations mimicking the abnormalities found in individuals with Apert syndrome, including dome-shaped skull, widely spaced eyes, premature closure of the coronal suture, and underdeveloped midface. However, coexpression of a small hairpin RNA targeting Fgfr2-S252W completely prevented these malformations and restored normal Fgfr2 signaling as shown by normal levels of Erk1 (601795)/Erk2 (176948) phosphorylation and reduced expression of Erk1 target genes. Furthermore, treatment of pregnant mice with a pharmacologic inhibitor of Mek1 (176872)/Mek2 (601263) blocked the phosphorylation and activation of Erk1/Erk2 and resulted in the recovery of Fgfr2-S252W mutant pups that were indistinguishable from wildtype. Shukla et al. (2007) concluded that ERK activation has a pathogenic role in the craniosynostosis resulting from the S252W substitution in FGFR2. </p><p>Targeted mutagenesis of Fgf9 (600921) in mice causes male-to-female sex reversal. Kim et al. (2007) found that targeted Fgfr2 deletion in mouse testis phenocopied Fgf9 knockout, suggesting that Fgfr2 is the Fgf9 receptor in mouse testis. The authors concluded that FGFR2 plays an essential role in testis determination. </p><p>Bagheri-Fam et al. (2015) studied the knockin Crouzon mouse model Fgfr2c(C342Y/C342Y) and observed partial male-to-female gonadal sex reversal, characterized by gonads that developed as ovotestes (containing both testicular and ovarian tissue). XY Fgfr2c(C342Y/-) ovaries showed reduced expression of Sertoli cell markers and FGF-responsive genes as well as increased expression of granulosa cell markers, compared to heterozygous XY Fgfr2c +/- knockout testes. In addition, the expression changes in XY Fgfr2c(C342Y/-) ovaries were restored to XY wildtype levels by the addition of the wildtype allele found in the heterozygous Crouzon model, supporting the C342Y mutant receptor showing loss-of-function activity in the gonads. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>44 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PFEIFFER SYNDROME, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, CYS342TYR
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<br />
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SNP: rs121918487,
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ClinVar: RCV000014173, RCV000014174, RCV000547490, RCV000762801, RCV001090933, RCV001196204, RCV001730471, RCV004795406
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 unrelated individuals with Crouzon syndrome (123500), Reardon et al. (1994) found a G-to-A transition at nucleotide 1037 in the B exon of the FGFR2 gene. This was predicted to result in a cys342-to-tyr (C342Y) substitution within the third Ig domain. The same mutation was found by Rutland et al. (1995) in a patient with Pfeiffer syndrome (101600), not Crouzon syndrome. </p><p>Steinberger et al. (1995) found mutations at codon 342 in 3 sporadic cases of Crouzon syndrome. Two of them were G-to-A transitions at position 1037, the mutation described by Reardon et al. (1994). The third was a C-to-G transversion at position 1038, resulting in replacement of cysteine by tryptophan (176943.0013). Steinberger et al. (1995) pointed out that a mutation in codon 342 had been found in 8 out of 17 cases of Crouzon syndrome and that in 9 cases the mutation occurred at 5 other positions, suggesting that codon 342 of exon B of the FGFR2 gene may be disposed to mutations in Crouzon syndrome. The substitutions of cysteine that appeared to be leading causes of Crouzon syndrome occur in the immunoglobulin-like domain of FGFR2. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PFEIFFER SYNDROME, INCLUDED<br />
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JACKSON-WEISS SYNDROME, INCLUDED<br />
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ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, CYS342ARG
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<br />
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SNP: rs121918488,
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ClinVar: RCV000014177, RCV000014178, RCV000014179, RCV000014180, RCV000534888, RCV001723565
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-C transition at nucleotide 1036 predicted to result in a cys342-to-arg (C342R) substitution in the FGFR2 protein. The mutation created a new restriction site which was not found in the clinically normal parents of this patient. The same mutation was found in 5 patients with Pfeiffer syndrome (101600), not Crouzon syndrome, by Rutland et al. (1995). As a possible explanation, they pointed to the occurrence of 2 different phenotypes from the asp178-to-asn substitution in the prion protein gene, depending on the amino acid present at position 129 in the product of the same allele. The same mutation was found by Park et al. (1995) in a sporadic case of Jackson-Weiss syndrome (123150). The patient showed corneal synostosis, hypertelorism with ocular proptosis, midface hypoplasia, deviated nasal septum, obligatory mouthbreathing, moderate hearing deficit with hypoplastic ear canals, wide great toes with medial deviation, and tarsal-metatarsal coalescence (calcaneocuboidal fusions and right fusion of the navicular and first cuneiform bones). No hand anomalies were present by clinical or radiographic examination. </p><p>In a patient with Antley-Bixler syndrome (ABS2; 207410), Reardon et al. (2000) identified the C342R substitution in the FGFR2 gene. The patient had normal male genitalia and a normal steroid profile. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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JACKSON-WEISS SYNDROME, INCLUDED<br />
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ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, CYS342SER
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<br />
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SNP: rs121918488,
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ClinVar: RCV000014181, RCV000014182, RCV000014183, RCV000415484, RCV000490034, RCV000655416
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a T-to-A transversion at nucleotide 1036 (the same as that involved in the cys342-to-arg mutation), predicting substitution of serine for cysteine (C342S). This mutation created a new restriction site which was not found in the unaffected parents. This same mutation was found in Jackson-Weiss syndrome (123150) by Tartaglia et al. (1997). The molecular basis for the phenotypic heterogeneity in the face of apparent genetic homogeneity is unclear. </p><p>In a patient with an 'extreme' Antley-Bixler phenotype (ABS2; 207410), Reardon et al. (2000) identified the C342S substitution in the FGFR2 gene. The patient had normal female genitalia and a normal steroid profile. </p><p>In a 15-year-old girl with Crouzon-like craniosynostosis and 46,XY complete gonadal dysgenesis, Bagheri-Fam et al. (2015) sequenced the candidate gene FGFR2 and identified heterozygosity for the C342S mutation. DNA from her parents was unavailable for study. Whole-exome sequencing to search for potential modifier variants influencing the proband's phenotype revealed single-nucleotide variants or indels in 193 genes. Bagheri-Fam et al. (2015) noted that although none of the changes were located in 63 genes associated with disorders of sex development, the patient did carry novel changes or indels in 35 genes that in mice are expressed in pre-Sertoli cells at the time of sex determination. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 CROUZON SYNDROME</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, TYR340HIS
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<br />
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SNP: rs121918489,
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ClinVar: RCV000014175, RCV001214882, RCV001723564
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a family with Crouzon syndrome (123500) in 5 generations, Reardon et al. (1994) found that affected members had a T-to-C transition at nucleotide 1030 predicted to cause a tyr340-to-his amino acid substitution in the gene product. All affected members of the family had the mutation; all unaffected members had the wildtype sequence. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, SER354CYS
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<br />
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SNP: rs121918490,
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ClinVar: RCV000014176, RCV000623131, RCV000655419, RCV001565300, RCV002287333
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a sporadic case of Crouzon syndrome (123500), Reardon et al. (1994) found a C-to-G transversion in nucleotide 1073, predicted to cause a ser354-to-cys amino acid change in the gene product. His parents had normal wildtype sequence. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 CROUZON SYNDROME</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
CRANIOSYNOSTOSIS, NONCLASSIFIABLE AUTOSOMAL DOMINANT, INCLUDED<br />
|
|
SCAPHOCEPHALY AND AXENFELD-RIEGER ANOMALY, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, ALA344ALA
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<br />
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|
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SNP: rs121918491,
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gnomAD: rs121918491,
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ClinVar: RCV000014184, RCV000014185, RCV000014186, RCV000192353, RCV000686210, RCV000762800, RCV001579726, RCV002247335, RCV002250460, RCV002280092, RCV002482864
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>On sequencing 2 individuals both from pedigrees with classic features of Crouzon syndrome (123500) and autosomal dominant transmission, Reardon et al. (1994) found a G-to-A transition at nucleotide 1044. This mutation would not result in an amino acid change as it involved the third base of an alanine codon, which raised the possibility that the particular change was simply a polymorphic variant. However, the same SSCP change was not found in any unaffected individual. Reardon et al. (1994) raised the possibility that the change of the codon from GCG to GCA created a cryptic splice site within the exon. </p><p>In the large Turkish family described by Steinberger et al. (1996), the phenotype of craniosynostosis varied greatly. Several persons with the mutation were healthy and had only mild facial findings such as slight hypertelorism and maxillary hypoplasia. Others were severely affected and their craniosynostoses caused increased intracranial pressure with complications such as severe headache and optic nerve compression. The pattern of premature cranial suture closure varied among the patients. Different timing and location of abnormal suture development resulted in phenotypic extremes such as dolichocephaly in 1 patient and brachycephaly in another. Only 1 patient in this family had broad great toes. </p><p>In a boy with scaphocephaly and an Axenfeld-Rieger anomaly, McCann et al. (2005) identified heterozygosity for the ala344-to-ala (A344A) mutation in the FGFR2 gene. The boy had no other dysmorphic features, and development was age appropriate; at age 6 years, he had no learning difficulties. </p><p>Using RNA from a patient with Crouzon syndrome in whom Jabs et al. (1994) had identified the A344A mutation, Li et al. (1995) demonstrated that the variant creates a new donor splice site, which results in a stable transcript and an altered receptor with a deletion in the Ig IIIc domain of FGFR2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 JACKSON-WEISS SYNDROME</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
CROUZON SYNDROME, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, ALA344GLY
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<br />
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|
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SNP: rs121918492,
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ClinVar: RCV000014187, RCV000014188, RCV001851846, RCV003313919
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Jabs et al. (1994) were prompted to examine the FGFR2 gene in the original Amish family with Jackson-Weiss syndrome (123150) because the clinical phenotype mapped to the same region, 10q25-q26, as FGFR2. They identified an ala344-to-gly mutation which resulted in a change just 2 residues away from the cysteine involved in the disulfide bond of the third immunoglobulin domain which dictates the ligand-binding specificity of FGFR2. The most distinctive and consistent feature of Jackson-Weiss syndrome is the abnormality of the feet: broad great toes with medial deviation and tarsal-metatarsal coalescence. When the classic manifestations of Crouzon syndrome (shallow orbits with ocular proptosis; 123500) are present in Jackson-Weiss syndrome, they are usually mild; Crouzon syndrome shows less variability of craniofacial abnormalities and no limb anomalies. The findings of Jabs et al. (1994) and Reardon et al. (1994) in these 2 craniosynostosis syndromes indicate the variability in manifestations of mutations in the same gene. </p><p>(Jabs et al. (1994) inadvertently cited the ala344-to-gly mutation as arg344-to-gly in one place and as ala342-to-gly in another place. The error was carried over into the table that accompanied the review by Mulvihill (1995).) </p><p>Gorry et al. (1995) found the ala344-to-gly mutation resulting from a C-to-G transversion at nucleotide 1043 of their FGFR2 clone in a patient with Crouzon syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0008 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, TYR328CYS
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<br />
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SNP: rs121918493,
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ClinVar: RCV000014189, RCV000798719, RCV004700231
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a familial case of Crouzon syndrome (123500), Jabs et al. (1994) identified a tyr328-to-cys mutation in the immunoglobulin domain. In this domain, a third cysteine may perturb the normal secondary loop structure that is created by the normal disulfide bond. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, SER347CYS
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<br />
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SNP: rs121918494,
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ClinVar: RCV000014190, RCV000626619, RCV000655421, RCV000726654, RCV001823713, RCV004813038
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a sporadic case of Crouzon syndrome (123500), Jabs et al. (1994) described a ser347-to-cys mutation. The introduction of a third cysteine in the immunoglobulin domain may perturb the normal secondary loop structure that is created by the normal disulfide bond. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0010 APERT SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
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ENDOMETRIAL CANCER, SOMATIC, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, SER252TRP
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<br />
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SNP: rs79184941,
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|
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gnomAD: rs79184941,
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|
|
|
ClinVar: RCV000014191, RCV000014192, RCV000263144, RCV000552015, RCV002476961, RCV004527288, RCV004532334, RCV004795407
|
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|
|
</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Apert Syndrome</em></strong></p><p>
|
|
In 25 unrelated patients with Apert syndrome (101200), Wilkie et al. (1995) identified a heterozygous 934C-G transversion in the FGFR2 gene, resulting in a ser252-to-trp (S252W) substitution within a highly conserved linker region between the second and third extracellular immunoglobulin (Ig) domains of the protein. The mutation occurs within a CpG dinucleotide and is adjacent to another FGFR2 mutation causing Apert syndrome (P253R; 176943.0011), and was predicted to affect the orientation of the binding domains and thus alter the binding of growth factors. </p><p>Among 70 unrelated patients with Apert syndrome, Slaney et al. (1996) found that 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly of the hands and feet was more severe in those with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. Slaney et al. (1996) suggested that the opposite trends for severity of syndactyly and cleft palate in relation to the 2 mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, which are ligands for FGFR2. </p><p>Passos-Bueno et al. (1998) reported a child whom they identified as having a Pfeiffer syndrome (101600)-like phenotype, without severe abnormalities of the upper and lower extremities, who had the S252W mutation. </p><p>By analysis of crystal structure, Ibrahimi et al. (2001) showed that both the S252W and P253R mutations associated with Apert syndrome introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity and resulting in a gain of function. </p><p>Mantilla-Capacho et al. (2005) reported a patient with Apert syndrome caused by the S252W mutation, which they stated resulted from a 755C-G transversion. The child did not have cleft palate, but did have preaxial polydactyly of the hands and feet. </p><p>From a cohort of 182 Spanish probands with craniosynostosis, Paumard-Hernandez et al. (2015) identified 23 patients with Apert syndrome and mutations in FGFR2, 15 of whom had the S252W variant. </p><p><strong><em>Endometrial Cancer, Somatic</em></strong></p><p>
|
|
Pollock et al. (2007) identified a somatic S252W mutation in 8 of 187 samples of endometrial carcinoma (608089), 7 of which were the endometrioid subtype and 1 of which was the serous subtype. It was the most common FGFR2 mutation identified. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0011 APERT SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, PRO253ARG
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<br />
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SNP: rs77543610,
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ClinVar: RCV000014193, RCV000489611, RCV000532721, RCV000762803, RCV001197223, RCV004532335
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 15 unrelated patients with Apert syndrome (101200), Wilkie et al. (1995) identified a heterozygous 937C-G transversion in the FGFR2 gene, resulting in a pro253-to-arg (P253R) substitution within a highly conserved linker region between the second and third extracellular immunoglobulin (Ig) domains of the protein. The P253R mutation is adjacent to another FGFR2 mutation causing Apert syndrome (S252W; 176943.0010), and was predicted to affect the orientation of the binding domains and thus alter the binding of growth factors. </p><p>Among 70 unrelated patients with Apert syndrome, Slaney et al. (1996) found that 45 had the S252W mutation and 25 had the P253R mutation. The syndactyly of the hands and feet was more severe in those with the P253R mutation. In contrast, cleft palate was significantly more common in patients with the S252W patients. No convincing differences were found in the prevalence of other malformations associated with Apert syndrome. Slaney et al. (1996) suggested that the opposite trends for severity of syndactyly and cleft palate in relation to the 2 mutations may relate to the varying patterns of temporal and tissue-specific expression of different fibroblast growth factors, which are ligands for FGFR2. </p><p>By analysis of crystal structure, Ibrahimi et al. (2001) showed that both the S252W and P253R mutations associated with Apert syndrome introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity and resulting in a gain of function. </p><p>Andreou et al. (2006) reported a 4-year-old girl with Apert syndrome associated with a heterozygous P253R mutation. She also developed a low-grade papillary urothelial carcinoma of the bladder. No FGFR3 (134934) mutations were identified in the bladder tumor. </p><p>From a cohort of 182 Spanish probands with craniosynostosis, Paumard-Hernandez et al. (2015) identified 23 patients Apert syndrome and mutations in FGFR2, 8 of whom had the S252W variant. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0012 PFEIFFER SYNDROME</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, THR341PRO
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<br />
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SNP: rs121918495,
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|
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ClinVar: RCV000014194, RCV001037961, RCV001781263
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a sporadic case of Pfeiffer syndrome (101600), Rutland et al. (1995) observed an A-to-C transversion at nucleotide 1033 changing thr to pro at position 341, adjacent to the cys342 residue that has been found altered in cases of Crouzon syndrome and Pfeiffer syndrome (e.g., 176943.0001). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0013 CROUZON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
FGFR2, CYS342TRP
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|
<br />
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|
|
SNP: rs121918496,
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|
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|
|
ClinVar: RCV000014195, RCV000535651, RCV001588812
|
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|
</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a sporadic case of Crouzon syndrome (123500), Steinberger et al. (1995) found a C-to-G transversion in nucleotide 1038, resulting in replacement of cysteine-343 by tryptophan. Ma et al. (1995) found the same mutation in a case of familial Crouzon syndrome. Studying 6 unrelated French families, they found in all of them evidence of close linkage to locus D10S1483 located on 10q25-q26. </p><p>Hollway et al. (1997) found this mutation in a mother/daughter pair. The mother had features of mild Crouzon syndrome, while her daughter had features of Pfeiffer syndrome. Both had the identical 1205C-G nucleotide substitution (1205C-G numbering is based on Dionne et al. (1990); 1038C-G is based on the Houssaint et al. (1990) sequence). The authors noted that other mutations in codon 342 are known to be accompanied by phenotypic variability: a G-to-A transition in codon 342 can result in either Crouzon syndrome or Pfeiffer syndrome (176943.0001), while a T-to-C transition in codon 342 can lead to Crouzon syndrome, Pfeiffer syndrome, or Jackson-Weiss syndrome (176943.0002). </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 CROUZON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
JACKSON-WEISS SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, GLN289PRO
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|
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|
<br />
|
|
|
|
SNP: rs121918497,
|
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|
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|
|
ClinVar: RCV000014196, RCV000014197, RCV000415509, RCV001217538, RCV001572560
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Crouzon syndrome (123500) kindred, Gorry et al. (1995) found a gln289-to-pro mutation due to an A-to-C transversion in nucleotide 878 in the 3-prime end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U), which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the gene. All previously reported Crouzon mutations had been found only in the FGFR2 spliceoform. Gorry et al. (1995) raised the question of possible second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes, which may determine specific aspects of the phenotypes of craniosynostosis syndromes. </p><p>In a patient with Jackson-Weiss syndrome, Meyers et al. (1996) identified heterozygosity for a 1045A-C transversion in exon IIIa of the FGFR2 gene, resulting in a gln289-to-pro (Q289P) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 BEARE-STEVENSON CUTIS GYRATA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
ENDOMETRIAL CANCER, SOMATIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, TYR375CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913478,
|
|
|
|
|
|
|
|
ClinVar: RCV000014198, RCV000014199, RCV000224124, RCV000549100, RCV000762799, RCV004532336
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Beare-Stevenson cutis gyrata syndrome (BSTVS; 123790) is an autosomal dominant disorder characterized by furrowed skin (cutis gyrata), acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities, and early death. Przylepa et al. (1996) detected FGFR2 mutations in this disorder. In 3 sporadic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; 2 had the identical tyr375-to-cys mutation in the transmembrane domain and 1 had a ser372-to-cys mutation (176943.0016) in the C-terminal end of the linker region between the immunoglobulin III-like and transmembrane domains. In 2 patients, neither of these mutations was found, suggesting to Przylepa et al. (1996) further genetic heterogeneity. </p><p>Wang et al. (2002) found the Y375C mutation in the FGFR2 gene in a Taiwanese patient with several clinical characteristics of Beare-Stevenson syndrome, including cutis gyrata, cloverleaf skull, prominent eyes, cleft palate, ear defects, and a protruding umbilical stump. </p><p>In 2 unrelated patients with Beare-Stevenson syndrome, Vargas et al. (2003) identified the Y375C mutation. Both presented at birth with craniofacial anomalies, variable cutis gyrata in forehead and preauricular regions, prominent umbilical stump, and anteriorly placed anus. Both required mechanical ventilation for respiratory support and died before 50 days of age. </p><p>Pollock et al. (2007) identified a somatic Y375C mutation in 2 unrelated samples of endometrial carcinoma (608089) of the endometrioid subtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 BEARE-STEVENSON CUTIS GYRATA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, SER372CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913477,
|
|
|
|
|
|
|
|
ClinVar: RCV000014200, RCV001382546
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>See 176943.0015 and Przylepa et al. (1996). </p><p>Fonseca et al. (2008) reported a girl with Beare-Stevenson cutis gyrata syndrome (BSTVS; 123790) who had a de novo heterozygous 1115C-G transversion in exon 11 of the FGFR2 gene, resulting in a ser372-to-cys (S372C) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 APERT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, SER252PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918498,
|
|
|
|
|
|
|
|
ClinVar: RCV000014201
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Apert syndrome (101200), Oldridge et al. (1997) identified a CG-to-TT change in the FGFR2 gene, resulting in a ser252-to-phe (S252F) substitution. This was said to be the first noncanonical mutation to be identified in Apert syndrome, its rarity being explained by the requirement for 2 residues of the serine codon to be mutated. </p><p>Lajeunie et al. (1999) identified the S252F substitution in a fetus with Apert syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 PFEIFFER SYNDROME VARIANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, SER252PHE AND PRO253SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs281865420,
|
|
|
|
|
|
|
|
ClinVar: RCV000014202
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Oldridge et al. (1997) identified a double amino acid substitution (ser252phe and pro253ser) resulting from a CGC-to-TCT mutation in the FGFR2 gene as the cause of a Pfeiffer syndrome (101600) variant. The clinical features in the isolated case were mild craniosynostosis, broad thumbs and big toes, fixed extension of several digits, and only minimal cutaneous syndactyly. The description of independent, complex nucleotide substitutions involving identical nucleotides (see 176943.0017) was unprecedented. Oldridge et al. (1997) speculated that this may result from functional selection of FGFR mutations in sperm. In both of these complex mutations, the 934C-T substitution was present. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, TRP290CYS
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918499,
|
|
|
|
|
|
|
|
ClinVar: RCV000014203, RCV002254264, RCV003150929, RCV004532337
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with severe Pfeiffer phenotype (101600), Tartaglia et al. (1997) reported a de novo 870G-C transversion in exon IIIa of the FGFR2 gene, resulting in a trp290-to-cys (W290C) mutation. The patient had cloverleaf skull deformity as well as the other typical ocular, hand, and foot anomalies seen in Pfeiffer syndrome. Missense mutations at codon 290 of FGFR2 had been reported previously in Crouzon syndrome, but not in Pfeiffer syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 CROUZON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, LYS292GLU
|
|
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|
|
<br />
|
|
|
|
SNP: rs121918500,
|
|
|
|
|
|
|
|
ClinVar: RCV000014204, RCV002513037
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 members of a 3-generation family with Crouzon syndrome (123500) and plagiocephaly, Steinberger et al. (1997) reported an A-to-G transition at nucleotide 886 in exon 5 of FGFR2, resulting in a lys292-to-glu substitution in Ig-like loop 3 of the gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 CROUZON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, TRP290ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918501,
|
|
|
|
|
|
|
|
ClinVar: RCV000014205, RCV000537718, RCV001549469
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>A trp290-to-arg substitution was observed by Oldridge et al. (1995) in a patient with classic Crouzon syndrome (123500). The amino acid substitution in this case resulted from a change of codon 290 from TGG (trp) to CGG (arg). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0022 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, TRP290GLY
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<br />
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SNP: rs121918501,
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ClinVar: RCV000014206, RCV004724741
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>A trp290-to-gly substitution was observed in an atypically mild form of Crouzon syndrome (123500) by Park et al. (1995). The amino acid substitution in this case resulted from a change of codon 290 from TGG (trp) to GGG (gly). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0023 SAETHRE-CHOTZEN SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, VAL-VAL DEL
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<br />
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SNP: rs879253718,
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ClinVar: RCV000014207
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a molecular study of 32 unrelated patients with features of Saethre-Chotzen syndrome (SCS; 101400), a common autosomal dominant condition of craniosynostosis and limb anomalies, Paznekas et al. (1998) found a single patient who had a val-val (codons 269 and 270) deletion in the FGFR2 gene. The patient had all the features, except digital anomalies, that occur in 33% or more of all patients with mutations in the TWIST1 gene (601622), which is the predominant site of mutations in this syndrome. The most common phenotypic features were coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability was present for either TWIST mutations or FGFR mutations. The overlapping clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition, such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes, supported the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans. Chun et al. (2002) stated that the photograph shown of this patient was at variance with Saethre-Chotzen syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0024 PFEIFFER SYNDROME, TYPE III</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ANTLEY-BIXLER SYNDROME WITHOUT GENITAL ANOMALIES OR DISORDERED STEROIDOGENESIS, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, SER351CYS
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<br />
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SNP: rs121918502,
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ClinVar: RCV000014208, RCV000014209, RCV000256107, RCV000415503, RCV000528973, RCV003313920, RCV004737152
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>Cohen (1993) defined 3 clinical subtypes of Pfeiffer syndrome (101600). Type I is the common 'classic' type, presenting with craniosynostosis and broad thumbs and first toes in patients with normal or near-normal intelligence. Soft tissue syndactyly, symphalangism, and elbow ankylosis may be present. This condition is compatible with survival and reproduction; thus it frequently is familial, inherited as an autosomal dominant. Pfeiffer syndrome type II is more severe than type I, presenting with cloverleaf skull due to pansynostosis, severe ocular proptosis, and central nervous system involvement; a variety of low-frequency abnormalities, such as intestinal malrotation and tracheal stenosis also occur in this disorder. Elbow ankylosis occurs with the highest frequency in this type. Because of early death and failure to reproduce, this phenotype has been observed only as a sporadic mutation. Similarly severely affected cases, but without cloverleaf skull, have been called Pfeiffer syndrome type III. Gripp et al. (1998) found a ser351-to-cys (S351C) mutation in the FGFR2 gene in a patient considered to have Pfeiffer syndrome type III. The patient had pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal nonrotation, and severe developmental delay. Skeletal abnormalities included bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The patient was unusual for the lack of broad thumbs. The patient most closely resembled one described by Kerr et al. (1996) as a case of Pfeiffer syndrome type III with normal thumbs. In a note added in proof, Gripp et al. (1998) stated that heterozygosity for a cys342-to-arg substitution (176943.0002) of the FGFR2 gene had been found in the patient reported by Kerr et al. (1996). Thus Pfeiffer syndrome appears to be heterogeneous. </p><p>Okajima et al. (1999) evaluated 3 unrelated patients with severe Crouzon or Pfeiffer syndrome. Two of them had ocular findings consistent with Peters anomaly, and the third patient had opaque corneae, thickened irides and ciliary bodies, and shallow anterior chambers with occluded angles. Craniosynostosis with and without cloverleaf skull deformity, large anterior fontanel, hydrocephalus, proptosis, depressed nasal bridge, choanal stenosis/atresia, midface hypoplasia, and elbow contractures were also present. These patients had airway compromise and seizures, and 2 died by age 15 months. All 3 cases were found to have the same FGFR2 S351C (1231C-to-G) mutation predicted to form an aberrant disulfide bond(s) and affect ligand binding. Seven patients with isolated Peters anomaly, 2 patients with Peters plus syndrome, and 3 cases of typical Antley-Bixler syndrome were screened for this mutation, but none was found. </p><p>In a patient with clinical manifestations that they found consistent with those of Antley-Bixler syndrome (ABS2; 207410), Chun et al. (1998) identified a heterozygous C-to-G transversion at nucleotide 1064 of the FGFR2 gene, resulting in an S351C substitution in the IgIII domain of the protein. In addition to craniosynostosis and elbow ankylosis, the patient presented with severe spinal dysraphism. Gorlin (1999) and Gripp et al. (1999) suggested that the patient of Chun et al. (1998) did not have Antley-Bixler syndrome but a nonspecific craniosynostosis syndrome. Chitayat and Chun (1999) in response reiterated the importance of looking for a mutation in the FGFR2 gene prior to informing parents that the recurrence risk of a similar condition is 25%. </p><p>In 3 patients with Antley-Bixler syndrome, Reardon et al. (2000) identified the S351C substitution in the FGFR2 gene. The patients all had normal-appearing genitalia, and the steroid profile was normal in the 2 patients in whom it was carried out. </p><p>In 3 fetuses diagnosed prenatally with severe Pfeiffer syndrome, Gonzales et al. (2005) identified heterozygosity for the S351C substitution in the FGFR2 gene. All 3 patients had a cartilaginous tracheal sleeve at autopsy with no visible tracheal rings. In addition, all had vertebral anomalies, including cervical, thoracic, and lumbar fusion, and sacrococcygeal eversion was also present in 2 cases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0025 APERT SYNDROME</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
|
FGFR2, ALU INS
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<br />
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|
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ClinVar: RCV000014210
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated patients with Apert syndrome (101200), Oldridge et al. (1999) identified a 360-bp insertion of an Alu-element involving exon 9 of the FGFR2 gene. The insertion was just upstream of exon 9 in 1 case and within exon 9 in the other case. Both insertions had arisen de novo and both occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth factor receptor (KGFR) domain and bacterially-expressed kinase domain, respectively), which are differentially expressed in mouse limbs on embryonic day 13. Oldridge et al. (1999) examined splicing of exon 9 in RNA extracted from fibroblasts and keratinocytes from 1 Apert syndrome patient with an Alu insertion and 2 patients with Pfeiffer syndrome (101600) who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provided the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0026 MOVED TO 176943.0017</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, ASP273DEL
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918503,
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|
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|
|
|
|
|
ClinVar: RCV000014211
|
|
|
|
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Pfeiffer syndrome type 2 (101600), Priolo et al. (2000) found an in-frame deletion of 3 bp (GAC), which removed aspartic acid at position 273 of the FGFR2 protein. The patient, when seen at 1 month of age, had severe trigonocephaly with cloverleaf skull, flat occipitus, downward displacement of the ears to a horizontal position with respect to the neck, and severe ocular proptosis. Also present were radial clinodactyly of the thumbs and valgus deviation of the halluces. Imaging studies showed progressive triventricular hydrocephalus, callosal dysgenesis, and Chiari I malformation (118420). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 CRANIOSYNOSTOSIS, NONSYNDROMIC UNICORONAL</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, ALA315SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918504,
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|
|
|
|
|
gnomAD: rs121918504,
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|
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|
|
|
ClinVar: RCV000014212, RCV000856813, RCV001280733, RCV001851847, RCV002496355
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Johnson et al. (2000) found a novel heterozygous mutation of the FGFR2 gene (943G-T, encoding the amino acid substitution ala315 to ser) in a girl with nonsyndromic unicoronal craniosynostosis. The mutation was also present in her mother and maternal grandfather who had mild facial asymmetry but did not have craniosynostosis. None of these individuals had the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history showed that the proband was in persistent breech presentation in utero and was delivered by cesarean section, at which time compression of the skull was apparent. Johnson et al. (2000) proposed that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case fetal head constraint associated with breech position) was necessary for craniosynostosis to occur. To their knowledge, this was the first report of an interaction between the weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
GASTRIC CANCER, SOMATIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, SER267PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918505,
|
|
|
|
|
|
|
|
ClinVar: RCV000014213, RCV000408850, RCV000435703, RCV000690962, RCV002508123
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Cornejo-Roldan et al. (1999) described a T-to-C transition at nucleotide 799 of the FGFR2 gene, resulting in a ser267-to-pro de novo mutation in each of 2 sporadic cases of Pfeiffer syndrome (101600). Jang et al. (2001) found the same change as a somatic mutation in gastric cancer (137215). Thus, a heterozygous somatic mutation identical to a germinal activating mutation in FGFR2 in a craniosynostosis syndrome resulted in cancer. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, IVSAS, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879253719,
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|
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|
|
|
|
|
ClinVar: RCV000014215, RCV000694780
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with a mild phenotype typical of classic Pfeiffer syndrome (101600) of subtype 1, including brachycephaly with coronal synostosis and hypertelorism, Teebi et al. (2002) identified a 952G-A transition at the -1 position of 3-prime acceptor site of exon IIIc of the FGFR2 gene. They found a different mutation at the same site in a patient with a severe Pfeiffer syndrome phenotype; see 176943.0031. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, 10-BP DEL/3-BP INS, NT952
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1589828632,
|
|
|
|
|
|
|
|
ClinVar: RCV000014216
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Teebi et al. (2002) described a complex deletion-insertion mutation at the 3-prime acceptor site of exon IIIc of the FGFR2 gene in a 17-year-old male with a severe Pfeiffer syndrome (101600) phenotype, within the spectrum of subtype 1, including severe ocular proptosis, elbow ankylosis, visceral anomalies, and normal intelligence. They found a different mutation at the same site in a patient with a mild Pfeiffer syndrome phenotype; see 176943.0030. </p><p>Wilkie (2002) pointed out that the expression of a distinct spliceoform of FGFR2 encoded by the alternatively spliced IIIb exon (termed FGFR2b or keratinocyte growth factor receptor) was demonstrated in fibroblasts from 5 patients with 3 different heterozygous mutations of this splice site (Oldridge et al., 1999; Tsukuno et al., 1999). These patients had diagnoses of Pfeiffer syndrome (4 cases) and Apert syndrome (1 case). In accordance with the guidelines for nomenclature suggested by den Dunnen and Antonarakis (2001), Wilkie (2002) clarified the designation for this mutation. The first nucleotide of exon IIIc is numbered 940. Based on this, the correct terminology for the indel mutation described by Teebi et al. (2002) should be c.940-3_946del10insACC. </p>
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CRANIOFACIAL-SKELETAL-DERMATOLOGIC DYSPLASIA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, TRP290CYS, 870G-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918499,
|
|
|
|
|
|
|
|
ClinVar: RCV000014217, RCV000014218, RCV000655418, RCV001268882, RCV002490362
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Whereas Tartaglia et al. (1997) described a trp290-to-cys (W290C) substitution arising from a G-to-C transversion in the FGFR2 gene (176943.0019) in a patient with severe Pfeiffer syndrome (101600), Schaefer et al. (1998) described a W290C mutation arising from a G-to-T transversion in a female infant diagnosed with Pfeiffer syndrome who had many overlapping features with Antley-Bixler syndrome (207410). </p><p>Shotelersuk et al. (2002) described a 15-year-old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies at T9-T12 as well as ankyloses of humeral-radial-ulnar joints, intercarpal joints, distal interphalangeal joints of the fifth fingers, fibulo-tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was heterozygous for an 870G-T change resulting in a W290C substitution in the extracellular domain of the FGFR2 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0033 PFEIFFER SYNDROME</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, GLU565ALA
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<br />
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SNP: rs121918506,
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ClinVar: RCV000014219, RCV001851848, RCV003441716, RCV004532338
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient with severe Pfeiffer syndrome (101600), Zankl et al. (2004) identified a heterozygous 1694A-C transversion in the FGFR2 gene, resulting in a glu565-to-ala (E565A) substitution in the tyrosine kinase (TK) domain of the protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0034 CROUZON SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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|
SCAPHOCEPHALY, MAXILLARY RETRUSION, AND IMPAIRED INTELLECTUAL DEVELOPMENT, INCLUDED (1 family)
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, LYS526GLU
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<br />
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SNP: rs121918507,
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ClinVar: RCV000014220, RCV000014221, RCV003988821, RCV004760330, RCV005089251
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and 2 daughters, de Ravel et al. (2005) identified a heterozygous 1576A-G transition in the FGFR2 gene, resulting in a lys526-to-glu (K526E) substitution in the tyrosine kinase I domain of the protein. The father and 1 of the daughters were diagnosed with Crouzon syndrome (123500), whereas the other daughter had neither facial dysmorphism nor hand or foot anomalies, indicating clinical nonpenetrance. </p><p>In all 11 affected members of a 3-generation family with scaphocephaly, maxillary retrusion, and impaired intellectual development (609579), McGillivray et al. (2005) identified heterozygosity for the 1576A-G transition in exon 14 of the FGFR2 gene, resulting in the K526E substitution. The mutation was not found in 19 unaffected family members. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0035 LADD SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FGFR2, ALA648THR
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<br />
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SNP: rs121918508,
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ClinVar: RCV000014222, RCV001291623, RCV002513038, RCV004767007
|
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|
</span>
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|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a Dutch family and an English family, Rohmann et al. (2006) found that LADD syndrome (LADD1; 149730) was associated with heterozygosity for a 1942G-A transition in exon 16 of the FGFR2 gene, predicting the substitution of a highly conserved ala648 by threonine (A648T). Rohmann et al. (2006) showed that the mutation probably originated independently in the 2 families, as it was not located on a common founder haplotype. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 LADD SYNDROME 1</strong>
|
|
</span>
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|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
FGFR2, 3-BP DEL, 1947AGA
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|
|
<br />
|
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|
|
SNP: rs879253720,
|
|
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|
|
|
|
|
ClinVar: RCV000014223
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish family with LADD syndrome (LADD1; 149730), Rohmann et al. (2006) found a heterozygous 3-bp deletion in exon 16 of the FGFR2 gene, delta1947-AGA-1949, that led to substitution of the highly conserved arginine at position 649 by serine and to the deletion of the neighboring aspartic acid (R649S delta-asp650). </p>
|
|
</span>
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|
</div>
|
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 LADD SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, ALA628THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918509,
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|
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|
|
ClinVar: RCV000014224, RCV000414415
|
|
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|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of LADD (LADD1; 149730) from Belgium, Rohmann et al. (2006) identified a de novo FGFR2 mutation, 1882G-A, that resulted in substitution of ala628 by thr (A628T). </p><p>Lew et al. (2007) presented the crystal structure of FGFR2 with the A628T mutation in complex with a nucleotide analog. The mutation altered the configuration of key residues in the catalytic pocket that are essential for substrate coordination, resulting in reduced tyrosine kinase activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0038 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
CROUZON SYNDROME, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, IVSDS, A-G, +3
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879253721,
|
|
|
|
|
|
|
|
ClinVar: RCV000014225, RCV000014226, RCV001254178, RCV001382547, RCV002273930
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Pfeiffer syndrome (101600), Cornejo-Roldan et al. (1999) identified a de novo 1084A-G transition at the +3 position (1084+3A-G) of the 5-prime donor site of exon IIIc of the FGFR2 gene. </p><p>In affected members of a family with mild features of Crouzon syndrome (123500), Kan et al. (2004) identified heterozygosity for the 1084+3A-G splice site transition in the FGFR2 gene. Although both A and G are consensus nucleotides at the +3 position of the 5-prime splice site, the authors calculated that the A-G substitution reduces the strength of the splice site and, using DNA sequencing and hybridization to specific oligonucleotides, demonstrated that the mutation causes a switch to the use of a known cryptic 5-prime splice site (see 176943.0006) within the upstream exon IIIc. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0039 PFEIFFER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, ASP321ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918510,
|
|
|
|
|
|
|
|
ClinVar: RCV000014227, RCV002513039
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Pfeiffer syndrome (101600) who had Apert syndrome (101200)-like syndactyly, Nagase et al. (1998) detected heterozygosity for an asp321-to-ala (D321A) amino acid substitution in FGFR2. The mutation occurs in the alternatively spliced beta-C-prime-beta-E loop of FGFR2c. </p><p>Heterozygosity for the D321A mutation had been described by Lajeunie et al. (1995) in a patient with Pfeiffer syndrome. The substitution resulted from a 974A-C transversion in the FGFR2 gene and was not found in 80 normal controls. </p><p>Ibrahimi et al. (2004) demonstrated that the D321A mutation increased the binding affinity of FGFR2c to multiple FGFs expressed in the cranial suture. Additionally, it violated FGFR2c ligand binding specificity and enabled this receptor to bind FGF10. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0040 BEARE-STEVENSON CUTIS GYRATA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, 63-BP DEL, NT1506
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554930637,
|
|
|
|
|
|
|
|
ClinVar: RCV000022731
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with Beare-Stevenson cutis gyrata syndrome (BSTVS; 123790), Slavotinek et al. (2009) identified a de novo heterozygous 63-bp deletion starting in exon 8 of the FGFR2 gene (1506del63), predicting the loss of 21 amino acids from the IgIIIa domain. Slavotinek et al. (2009) suggested that the deletion may alter the splicing of isoform IIIc, resulting in illegitimate expression and thus a gain of function of FGFR2b. Striking craniofacial features were present at birth, including cloverleaf skull with fused sutures, ocular proptosis with hypoplasia of the supraorbital ridges, hypertelorism, strabismus, deep creases below the eyes, a high nasal bridge, midface hypoplasia, high-arched and narrow palate, and bilateral ear creases. Cutaneous features included cutis gyrata and acanthosis nigricans of the posterior scalp, small skin tags, excess neck skin, and a prominent umbilicus with redundant skin. Hydrocephalus with Arnold-Chiari malformation was present, but neurodevelopment was normal. Unusual features included multiple neonatal teeth, gingival hyperplasia, and atresia of the external ear canals. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0041 CROUZON SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, ALA337PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906676,
|
|
|
|
|
|
|
|
ClinVar: RCV000022732, RCV002513173
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Brazilian patient with Crouzon syndrome (123500), Passos-Bueno et al. (1998) identified a heterozygous 1188G-C transversion in exon IIIc of the FGFR2 gene, resulting in an ala337-to-pro (A337P) substitution in a conserved residue. The mutation was not found in 40 control chromosomes. Functional studies were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, ALA337THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906676,
|
|
|
|
|
|
|
|
ClinVar: RCV000022733
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant is classified as a variant of unknown significance because its contribution to a craniosynostosis phenotype has not been confirmed.</p><p>Wilkie et al. (2007) identified a heterozygous 1009G-A transition in the FGFR2 gene, resulting in an ala337-to-thr (A337T) substitution, in a child with left unicoronal synostosis. She did not have Crouzonoid or other syndromic features. However, the same mutation was found in 6 additional family members without craniosynostosis, although 1 had midface hypoplasia and crowded teeth. Wilkie et al. (2007) noted that a mutation affecting the same codon (A337P; 176943.0041) had been identified in a patient with Crouzon syndrome (123500), suggesting that the A337T variant may be causally related to the phenotype in the proband with unicoronal synostosis. However, no functional studies were performed on the A337T variant. Wilkie et al. (2007) concluded that A337T showed either reduced penetrance or was of uncertain pathogenicity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 BENT BONE DYSPLASIA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, MET391ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906677,
|
|
|
|
|
|
|
|
ClinVar: RCV000022734, RCV000493423
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 1 male and 2 female fetuses with a perinatal lethal bent bone dysplasia syndrome-1 (BBDS1; 614592), Merrill et al. (2012) identified heterozygosity for a de novo 1172T-G transversion in exon 9 of the FGFR2 gene, resulting in a met391-to-arg (M391R) substitution that replaces a highly conserved hydrophobic residue with a positively charged polar amino acid in the transmembrane domain. The mutation was not present in parental DNA available from 2 of the cases, and was not found in 210 ethnically matched control alleles. Using diseased chondrocytes and a cell-based assay, Merrill et al. (2012) demonstrated that the M391R mutation selectively reduces plasma-membrane levels of FGFR2 and markedly diminishes the receptor's responsiveness to extracellular FGF (136350). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 BENT BONE DYSPLASIA SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FGFR2, TYR381ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906678,
|
|
|
|
|
|
|
|
ClinVar: RCV000022735, RCV000190765, RCV000725446, RCV004528130
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a female fetus with a perinatal lethal bent bone dysplasia syndrome-1 (BBDS1; 614592), Merrill et al. (2012) identified heterozygosity for a 1141T-G transversion in exon 9 of the FGFR2 gene, resulting in a tyr381-to-asp (Y381D) substitution that replaces a highly conserved hydrophobic residue with a negatively charged polar amino acid in the transmembrane domain. Parental DNA was unavailable, but the mutation was not found in 210 ethnically matched control alleles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
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Contributors:
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Marla J. F. O'Neill - updated : 01/25/2022<br>Marla J. F. O'Neill - updated : 3/18/2016<br>Ada Hamosh - updated : 4/11/2014<br>Marla J. F. O'Neill - updated : 4/24/2012<br>Cassandra L. Kniffin - updated : 1/4/2012<br>George E. Tiller - updated : 12/2/2011<br>Cassandra L. Kniffin - updated : 7/18/2011<br>George E. Tiller - updated : 3/31/2010<br>George E. Tiller - updated : 10/15/2009<br>Marla J. F. O'Neill - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 4/28/2008<br>Cassandra L. Kniffin - updated : 4/7/2008<br>Patricia A. Hartz - updated : 2/27/2008<br>Patricia A. Hartz - updated : 2/7/2008<br>Cassandra L. Kniffin - updated : 10/29/2007<br>Patricia A. Hartz - updated : 9/25/2007<br>Cassandra L. Kniffin - updated : 7/17/2007<br>Marla J. F. O'Neill - updated : 4/30/2007<br>Marla J. F. O'Neill - updated : 4/17/2007<br>George E. Tiller - updated : 4/5/2007<br>Marla J. F. O'Neill - updated : 3/13/2007<br>Cassandra L. Kniffin - updated : 12/18/2006<br>Cassandra L. Kniffin - updated : 7/11/2006<br>Marla J. F. O'Neill - updated : 5/24/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Marla J. F. O'Neill - updated : 4/6/2006<br>Cassandra L. Kniffin - updated : 2/8/2006<br>Patricia A. Hartz - updated : 12/7/2005<br>Victor A. McKusick - updated : 11/17/2005<br>Marla J. F. O'Neill - updated : 10/25/2005<br>Marla J. F. O'Neill - updated : 9/13/2005<br>Marla J. F. O'Neill - updated : 9/1/2005<br>Victor A. McKusick - updated : 4/26/2005<br>Victor A. McKusick - updated : 1/3/2005<br>Marla J. F. O'Neill - updated : 7/9/2004<br>Patricia A. Hartz - updated : 4/21/2004<br>Victor A. McKusick - updated : 2/13/2004<br>Victor A. McKusick - updated : 10/7/2003<br>Victor A. McKusick - updated : 8/25/2003<br>Ada Hamosh - updated : 8/12/2003<br>Victor A. McKusick - updated : 4/28/2003<br>Ada Hamosh - updated : 4/22/2003<br>Victor A. McKusick - updated : 11/7/2002<br>Victor A. McKusick - updated : 8/14/2002<br>Victor A. McKusick - updated : 8/8/2002<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 1/17/2002<br>Victor A. McKusick - updated : 9/19/2001<br>Victor A. McKusick - updated : 9/12/2001<br>Victor A. McKusick - updated : 8/1/2001<br>Victor A. McKusick - updated : 6/26/2001<br>Victor A. McKusick - updated : 4/17/2001<br>Victor A. McKusick - updated : 1/12/2001<br>Victor A. McKusick - updated : 11/2/2000<br>Ada Hamosh - updated : 10/25/2000<br>Victor A. McKusick - updated : 9/1/2000<br>Stylianos E. Antonarakis - updated : 6/7/2000<br>Victor A. McKusick - updated : 4/10/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Ada Hamosh - updated : 9/21/1999<br>Victor A. McKusick - updated : 7/20/1999<br>Victor A. McKusick - updated : 4/26/1999<br>Ada Hamosh - updated : 4/19/1999<br>Victor A. McKusick - updated : 2/5/1999<br>Michael J. Wright - updated : 11/16/1998<br>Victor A. McKusick - updated : 10/8/1998<br>Victor A. McKusick - updated : 9/17/1998<br>Victor A. McKusick - updated : 9/1/1998<br>Victor A. McKusick - updated : 7/1/1998<br>Clair A. Francomano - updated : 6/26/1998<br>Victor A. McKusick - updated : 6/11/1998<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 3/25/1998<br>Michael J. Wright - updated : 11/20/1997<br>Victor A. McKusick - updated : 10/14/1997<br>Ada Hamosh - updated : 7/10/1997<br>Victor A. McKusick - updated : 2/28/1997<br>Victor A. McKusick - updated : 2/17/1997<br>Moyra Smith - updated : 1/31/1997<br>Moyra Smith - updated : 1/31/1997<br>Moyra Smith - updated : 4/26/1996
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Creation Date:
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Victor A. McKusick : 11/19/1990
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carol : 01/07/2023<br>carol : 11/04/2022<br>carol : 11/02/2022<br>carol : 11/01/2022<br>carol : 10/13/2022<br>carol : 01/25/2022<br>carol : 09/17/2018<br>alopez : 08/13/2018<br>carol : 08/10/2018<br>alopez : 08/09/2018<br>carol : 09/06/2016<br>joanna : 07/18/2016<br>alopez : 3/18/2016<br>alopez : 4/10/2015<br>alopez : 4/11/2014<br>terry : 4/1/2013<br>terry : 10/10/2012<br>carol : 9/19/2012<br>carol : 6/5/2012<br>carol : 5/1/2012<br>carol : 4/25/2012<br>terry : 4/24/2012<br>alopez : 4/12/2012<br>carol : 2/2/2012<br>ckniffin : 1/4/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>wwang : 7/22/2011<br>ckniffin : 7/18/2011<br>terry : 11/16/2010<br>alopez : 9/24/2010<br>terry : 5/28/2010<br>wwang : 4/14/2010<br>terry : 3/31/2010<br>carol : 3/16/2010<br>carol : 3/16/2010<br>carol : 3/15/2010<br>wwang : 10/16/2009<br>terry : 10/15/2009<br>wwang : 9/4/2009<br>terry : 8/27/2009<br>wwang : 9/9/2008<br>wwang : 5/1/2008<br>ckniffin : 4/28/2008<br>wwang : 4/9/2008<br>ckniffin : 4/7/2008<br>wwang : 2/27/2008<br>mgross : 2/7/2008<br>terry : 2/7/2008<br>wwang : 11/16/2007<br>ckniffin : 10/29/2007<br>alopez : 9/25/2007<br>terry : 9/20/2007<br>carol : 8/17/2007<br>ckniffin : 7/17/2007<br>wwang : 6/13/2007<br>wwang : 4/30/2007<br>wwang : 4/17/2007<br>alopez : 4/16/2007<br>alopez : 4/13/2007<br>terry : 4/5/2007<br>wwang : 3/14/2007<br>terry : 3/13/2007<br>wwang : 12/27/2006<br>ckniffin : 12/18/2006<br>wwang : 7/31/2006<br>ckniffin : 7/11/2006<br>carol : 6/9/2006<br>wwang : 5/31/2006<br>terry : 5/24/2006<br>alopez : 5/1/2006<br>alopez : 5/1/2006<br>terry : 4/27/2006<br>wwang : 4/6/2006<br>terry : 4/6/2006<br>carol : 4/6/2006<br>ckniffin : 2/8/2006<br>alopez : 2/3/2006<br>wwang : 12/7/2005<br>terry : 12/7/2005<br>alopez : 11/29/2005<br>terry : 11/17/2005<br>wwang : 10/27/2005<br>terry : 10/25/2005<br>carol : 9/14/2005<br>terry : 9/13/2005<br>carol : 9/1/2005<br>carol : 8/30/2005<br>carol : 8/30/2005<br>terry : 8/3/2005<br>tkritzer : 4/29/2005<br>terry : 4/26/2005<br>tkritzer : 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5/9/2001<br>mcapotos : 5/8/2001<br>mcapotos : 4/25/2001<br>terry : 4/17/2001<br>cwells : 1/25/2001<br>terry : 1/12/2001<br>carol : 1/8/2001<br>mcapotos : 11/13/2000<br>terry : 11/2/2000<br>alopez : 10/25/2000<br>mcapotos : 9/8/2000<br>mcapotos : 9/7/2000<br>terry : 9/1/2000<br>mgross : 6/7/2000<br>mcapotos : 5/4/2000<br>mcapotos : 5/3/2000<br>terry : 4/10/2000<br>terry : 11/30/1999<br>alopez : 11/15/1999<br>terry : 11/9/1999<br>carol : 9/21/1999<br>jlewis : 8/2/1999<br>jlewis : 8/2/1999<br>terry : 7/20/1999<br>alopez : 5/10/1999<br>terry : 4/26/1999<br>alopez : 4/20/1999<br>alopez : 4/19/1999<br>alopez : 4/19/1999<br>alopez : 4/19/1999<br>carol : 3/3/1999<br>mgross : 2/12/1999<br>mgross : 2/10/1999<br>terry : 2/5/1999<br>carol : 1/5/1999<br>dkim : 12/11/1998<br>alopez : 12/8/1998<br>terry : 11/16/1998<br>dkim : 10/13/1998<br>carol : 10/12/1998<br>terry : 10/8/1998<br>carol : 9/21/1998<br>terry : 9/17/1998<br>carol : 9/2/1998<br>terry : 9/1/1998<br>carol : 7/1/1998<br>carol : 6/26/1998<br>terry : 6/23/1998<br>terry : 6/19/1998<br>carol : 6/12/1998<br>terry : 6/11/1998<br>alopez : 5/14/1998<br>psherman : 4/15/1998<br>alopez : 4/1/1998<br>alopez : 3/25/1998<br>terry : 3/17/1998<br>alopez : 12/5/1997<br>alopez : 12/3/1997<br>alopez : 11/25/1997<br>terry : 11/20/1997<br>jenny : 10/21/1997<br>terry : 10/14/1997<br>alopez : 7/30/1997<br>alopez : 7/10/1997<br>alopez : 7/10/1997<br>alopez : 6/2/1997<br>mark : 2/28/1997<br>terry : 2/26/1997<br>mark : 2/17/1997<br>terry : 2/11/1997<br>terry : 1/31/1997<br>mark : 1/31/1997<br>mark : 1/31/1997<br>jamie : 1/21/1997<br>terry : 1/15/1997<br>jenny : 1/7/1997<br>mark : 12/26/1996<br>mark : 8/27/1996<br>mark : 8/15/1996<br>mark : 8/15/1996<br>mark : 8/7/1996<br>terry : 8/6/1996<br>terry : 8/2/1996<br>terry : 5/3/1996<br>carol : 4/26/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 3/3/1996<br>terry : 2/27/1996<br>mark : 1/10/1996<br>mark : 1/4/1996<br>mark : 9/7/1995<br>carol : 3/2/1995<br>terry : 2/13/1995<br>jason : 7/1/1994<br>carol : 6/23/1992<br>supermim : 3/16/1992
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